@article{pmid16199668,

title = {NMR structure of the conserved hypothetical protein TM0487 from Thermotoga maritima: implications for 216 homologous DUF59 proteins},

author = {Marcius S Almeida and Torsten Herrmann and Wolfgang Peti and Ian A Wilson and Kurt Wüthrich},

doi = {10.1110/ps.051755805},

issn = {0961-8368},

year  = {2005},

date = {2005-11-01},

journal = {Protein Sci},

volume = {14},

number = {11},

pages = {2880--2886},

abstract = {The NMR structure of the conserved hypothetical protein TM0487 from Thermotoga maritima represents an alpha/beta-topology formed by the regular secondary structures alpha1-beta1-beta2-alpha2-beta3-beta4-alpha3- beta5-3(10)-alpha4, with a small anti-parallel beta-sheet of beta-strands 1 and 2, and a mixed parallel/anti-parallel beta-sheet of beta-strands 3-5. Similar folds have previously been observed in other proteins, with amino acid sequence identity as low as 3% and a variety of different functions. There are also 216 sequence homologs of TM0487, which all have the signature sequence of domains of unknown function 59 (DUF59), for which no three-dimensional structures have as yet been reported. The TM0487 structure thus presents a platform for homology modeling of this large group of DUF59 proteins. Conserved among most of the DUF59s are 13 hydrophobic residues, which are clustered in the core of TM0487. A putative active site of TM0487 consisting of residues D20, E22, L23, T51, T52, and C55 is conserved in 98 of the 216 DUF59 sequences. Asp20 is buried within the proposed active site without any compensating positive charge, which suggests that its pK(a) value may be perturbed. Furthermore, the DUF59 family includes ORFs that are part of a conserved chromosomal group of proteins predicted to be involved in Fe-S cluster metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16104018,

title = {Crystal structure of the global regulatory protein CsrA from Pseudomonas putida at 2.05 A resolution reveals a new fold},

author = {Chris Rife and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Herbert Axelrod and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Lukasz Jaroszewski and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Mitchell D Miller and Kin Moy and Edward Nigoghossian and Jessica Paulsen and Kevin Quijano and Ron Reyes and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Aprilfawn White and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20502},

issn = {1097-0134},

year  = {2005},

date = {2005-11-01},

journal = {Proteins},

volume = {61},

number = {2},

pages = {449--453},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16167343,

title = {Crystal structure of Hsp33 chaperone (TM1394) from Thermotoga maritima at 2.20 A resolution},

author = {Lukasz Jaroszewski and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Sanjay Agarwalla and Eileen Ambing and Herbert Axelrod and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Mitchell D Miller and Kin Moy and Edward Nigoghossian and Jessica Paulsen and Kevin Quijano and Ron Reyes and Chris Rife and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Aprilfawn White and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20542},

issn = {1097-0134},

year  = {2005},

date = {2005-11-01},

journal = {Proteins},

volume = {61},

number = {3},

pages = {669--673},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16284180,

title = {Structure of a V3-containing HIV-1 gp120 core},

author = {Chih-chin Huang and Min Tang and Mei-Yun Zhang and Shahzad Majeed and Elizabeth Montabana and Robyn L Stanfield and Dimiter S Dimitrov and Bette Korber and Joseph Sodroski and Ian A Wilson and Richard Wyatt and Peter D Kwong},

doi = {10.1126/science.1118398},

issn = {1095-9203},

year  = {2005},

date = {2005-11-01},

journal = {Science},

volume = {310},

number = {5750},

pages = {1025--1028},

abstract = {The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16104019,

title = {Crystal structure of a putative modulator of DNA gyrase (pmbA) from Thermotoga maritima at 1.95 A resolution reveals a new fold},

author = {Chris Rife and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Herbert Axelrod and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Lukasz Jaroszewski and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Mitchell D Miller and Kin Moy and Edward Nigoghossian and Jessica Paulsen and Kevin Quijano and Ron Reyes and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Aprilfawn White and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20468},

issn = {1097-0134},

year  = {2005},

date = {2005-11-01},

journal = {Proteins},

volume = {61},

number = {2},

pages = {444--448},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16219699,

title = {Antibody vs. HIV in a clash of evolutionary titans},

author = {Dennis R Burton and Robyn L Stanfield and Ian A Wilson},

doi = {10.1073/pnas.0505126102},

issn = {0027-8424},

year  = {2005},

date = {2005-10-01},

journal = {Proc Natl Acad Sci U S A},

volume = {102},

number = {42},

pages = {14943--14948},

abstract = {HIV has evolved many strategies to avoid neutralizing antibody responses, particularly to conserved regions on the external glycoprotein spikes of the virus. Nevertheless, a small number of antibodies have been evolved by the human immune system to recognize conserved parts of the glycoproteins, and therefore, have broadly neutralizing cross-strain activities. These antibodies constitute important tools in the quest to design immunogens that can elicit broadly neutralizing antibodies in humans and hence contribute to an effective HIV vaccine. Crystallographic analyses of the antibodies, in many cases in an antigen-complexed form, have revealed novel and, in some instances, remarkable structural adaptations to attain virus recognition. Antibodies, like HIV, can evolve relatively rapidly through mutation and selection. It seems that the structures of these broadly neutralizing antibodies bear witness to a heroic struggle between two titans of rapid evolution.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16140327,

title = {Crystal structure of viral macrophage inflammatory protein I encoded by Kaposi's sarcoma-associated herpesvirus at 1.7A},

author = {John G Luz and Minmin Yu and Ying Su and Zining Wu and Zhou Zhou and Ren Sun and Ian A Wilson},

doi = {10.1016/j.jmb.2005.08.011},

issn = {0022-2836},

year  = {2005},

date = {2005-10-01},

journal = {J Mol Biol},

volume = {352},

number = {5},

pages = {1019--1028},

abstract = {Viral macrophage inflammatory protein I (vMIP-I) is a chemokine encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) that selectively activates the CC chemokine receptor 8 (CCR8), for which the endogenous ligand is CCL1. The crystal structure of vMIP-I was determined at 1.7A for comparison with other chemokines, especially those that bind CCR8, such as vMIP-II from KSHV, a CCR8 antagonist and the closest homolog (40% identical). vMIP-I has a typical chemokine fold consisting of an extended N-terminal loop, followed by a three-stranded antiparallel beta-sheet and a C-terminal alpha-helix. The four molecules in the asymmetric unit comprise two MIP-1beta-like dimers. Electrostatic surface representations of CCR8-binding chemokines reveal only minor areas of correlating surface potential, which must be reconciled with promiscuity in receptor and glycosaminoglycan (GAG) binding. In addition, the biological relevance of chemokine oligomerization is examined by comparing the oligomeric states of all chemokine structures deposited to date in the RCSB PDB.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16174734,

title = {Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12},

author = {Daniel A Calarese and Hing-Ken Lee and Cheng-Yuan Huang and Michael D Best and Rena D Astronomo and Robyn L Stanfield and Hermann Katinger and Dennis R Burton and Chi-Huey Wong and Ian A Wilson},

doi = {10.1073/pnas.0505763102},

issn = {0027-8424},

year  = {2005},

date = {2005-09-01},

journal = {Proc Natl Acad Sci U S A},

volume = {102},

number = {38},

pages = {13372--13377},

abstract = {Human antibody 2G12 neutralizes a broad range of HIV-1 isolates. Hence, molecular characterization of its epitope, which corresponds to a conserved cluster of oligomannoses on the viral envelope glycoprotein gp120, is a high priority in HIV vaccine design. A prior crystal structure of 2G12 in complex with Man(9)GlcNAc(2) highlighted the central importance of the D1 arm in antibody binding. To characterize the specificity of 2G12 more precisely, we performed solution-phase ELISA, carbohydrate microarray analysis, and cocrystallized Fab 2G12 with four different oligomannose derivatives (Man(4), Man(5), Man(7), and Man(8)) that compete with gp120 for binding to 2G12. Our combined studies reveal that 2G12 is capable of binding both the D1 and D3 arms of the Man(9)GlcNAc(2) moiety, which would provide more flexibility to make the required multivalent interactions between the antibody and the gp120 oligomannose cluster than thought previously. These results have important consequences for the design of immunogens to elicit 2G12-like neutralizing antibodies as a component of an HIV vaccine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16001405,

title = {Crystal structure of an Apo mRNA decapping enzyme (DcpS) from Mouse at 1.83 A resolution},

author = {Gye Won Han and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Herbert Axelrod and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Justin Haugen and Michael Hornsby and Lukasz Jaroszewski and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Timothy M McPhillips and Mitchell D Miller and Kin Moy and Edward Nigoghossian and Jessica Paulsen and Kevin Quijano and Ron Reyes and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Aprilfawn White and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20467},

issn = {1097-0134},

year  = {2005},

date = {2005-09-01},

journal = {Proteins},

volume = {60},

number = {4},

pages = {797--802},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16103207,

title = {A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity},

author = {Laurel Glaser and James Stevens and Dmitriy Zamarin and Ian A Wilson and Adolfo García-Sastre and Terrence M Tumpey and Christopher F Basler and Jeffery K Taubenberger and Peter Palese},

doi = {10.1128/JVI.79.17.11533-11536.2005},

issn = {0022-538X},

year  = {2005},

date = {2005-09-01},

journal = {J Virol},

volume = {79},

number = {17},

pages = {11533--11536},

abstract = {The receptor binding specificity of influenza viruses may be important for host restriction of human and avian viruses. Here, we show that the hemagglutinin (HA) of the virus that caused the 1918 influenza pandemic has strain-specific differences in its receptor binding specificity. The A/South Carolina/1/18 HA preferentially binds the alpha2,6 sialic acid (human) cellular receptor, whereas the A/New York/1/18 HA, which differs by only one amino acid, binds both the alpha2,6 and the alpha2,3 sialic acid (avian) cellular receptors. Compared to the conserved consensus sequence in the receptor binding site of avian HAs, only a single amino acid at position 190 was changed in the A/New York/1/18 HA. Mutation of this single amino acid back to the avian consensus resulted in a preference for the avian receptor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16007091,

title = {Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor},

author = {Dirk M Zajonc and Carlos Cantu and Jochen Mattner and Dapeng Zhou and Paul B Savage and Albert Bendelac and Ian A Wilson and Luc Teyton},

doi = {10.1038/ni1224},

issn = {1529-2908},

year  = {2005},

date = {2005-08-01},

journal = {Nat Immunol},

volume = {6},

number = {8},

pages = {810--818},

abstract = {Natural killer T cells express a conserved, semi-invariant alphabeta T cell receptor that has specificity for self glycosphingolipids and microbial cell wall alpha-glycuronosylceramide antigens presented by CD1d molecules. Here we report the crystal structure of CD1d in complex with a short-chain synthetic variant of alpha-galactosylceramide at a resolution of 2.2 A. This structure elucidates the basis for the high specificity of these microbial ligands and explains the restriction of the alpha-linkage as a unique pathogen-specific pattern-recognition motif. Comparison of the binding of altered lipid ligands to CD1d and T cell receptors suggested that the differential T helper type 1-like and T helper type 2-like properties of natural killer T cells may originate largely from differences in their 'loading' in different cell types and hence in their tissue distribution in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15961631,

title = {Crystal structure of human toll-like receptor 3 (TLR3) ectodomain},

author = {Jungwoo Choe and Matthew S Kelker and Ian A Wilson},

doi = {10.1126/science.1115253},

issn = {1095-9203},

year  = {2005},

date = {2005-07-01},

journal = {Science},

volume = {309},

number = {5734},

pages = {581--585},

abstract = {Toll-like receptors (TLRs) play key roles in activating immune responses during infection. The human TLR3 ectodomain structure at 2.1 angstroms reveals a large horseshoe-shaped solenoid assembled from 23 leucine-rich repeats (LRRs). Asparagines conserved in the 24-residue LRR motif contribute extensive hydrogen-bonding networks for solenoid stabilization. TLR3 is largely masked by carbohydrate, but one face is glycosylation-free, which suggests its potential role in ligand binding and oligomerization. Highly conserved surface residues and a TLR3-specific LRR insertion form a homodimer interface in the crystal, whereas two patches of positively charged residues and a second insertion would provide an appropriate binding site for double-stranded RNA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16002697,

title = {Crystal structure of mouse CD1d bound to the self ligand phosphatidylcholine: a molecular basis for NKT cell activation},

author = {Barbara Giabbai and Stèphane Sidobre and M D Max Crispin and Yovan Sanchez-Ruìz and Angela Bachi and Mitchell Kronenberg and Ian A Wilson and Massimo Degano},

doi = {10.4049/jimmunol.175.2.977},

issn = {0022-1767},

year  = {2005},

date = {2005-07-01},

journal = {J Immunol},

volume = {175},

number = {2},

pages = {977--984},

abstract = {NKT cells are immunoregulatory lymphocytes whose activation is triggered by the recognition of lipid Ags in the context of the CD1d molecules by the TCR. In this study we present the crystal structure to 2.8 A of mouse CD1d bound to phosphatidylcholine. The interactions between the ligand acyl chains and the CD1d molecule define the structural and chemical requirements for the binding of lipid Ags to CD1d. The orientation of the polar headgroup toward the C terminus of the alpha1 helix provides a rationale for the structural basis for the observed Valpha chain bias in invariant NKT cells. The contribution of the ligand to the protein surface suggests a likely mode of recognition of lipid Ags by the NKT cell TCR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15886110,

title = {T-cell activation by lipopeptide antigens},

author = {Ildiko Van Rhijn and Dirk M Zajonc and Ian A Wilson and D Branch Moody},

doi = {10.1016/j.coi.2005.04.006},

issn = {0952-7915},

year  = {2005},

date = {2005-06-01},

journal = {Curr Opin Immunol},

volume = {17},

number = {3},

pages = {222--229},

abstract = {The discovery of the CD1 antigen-presenting system reveals that T cells survey the lipid content of target cells via T-cell receptor (TCR) contact with CD1 bound to lipids, glycolipids and small molecules. Recently, CD1 proteins have been found to present mycobacterial lipopeptides that are involved in scavenging iron from infected cells. The mechanism of lipopeptide antigen presentation by CD1 involves the anchoring of antigens in the hydrophobic binding groove, resulting in exposure of the peptide moiety for TCR contact. These findings expand the range of known antigens for T cells and raise the intriguing possibility that CD1, similar to MHC class I and II molecules, enables T cells to discriminate among peptide sequences.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15822122,

title = {Crystal structure of an indigoidine synthase A (IndA)-like protein (TM1464) from Thermotoga maritima at 1.90 A resolution reveals a new fold},

author = {Inna Levin and Mitchell D Miller and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Tanya Biorac and Jamison Cambell and Jaume M Canaves and Hsiu-Ju Chiu and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Lukasz Jaroszewski and Cathy Karlak and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Andrew Morse and Kin Moy and Edward Nigoghossian and Jie Ouyang and Rebecca Page and Kevin Quijano and Ron Reyes and Alyssa Robb and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Xianhong Wang and Bill West and Guenter Wolf and Qingping Xu and Olga Zagnitko and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20420},

issn = {1097-0134},

year  = {2005},

date = {2005-06-01},

journal = {Proteins},

volume = {59},

number = {4},

pages = {864--868},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15822125,

title = {Crystal structure of S-adenosylmethionine:tRNA ribosyltransferase-isomerase (QueA) from Thermotoga maritima at 2.0 A resolution reveals a new fold},

author = {Irimpan Mathews and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Herbert Axelrod and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Lukasz Jaroszewski and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Inna Levin and Mitchell D Miller and Kin Moy and Edward Nigoghossian and Jie Ouyang and Jessica Paulsen and Kevin Quijano and Ron Reyes and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Aprilfawn White and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20419},

issn = {1097-0134},

year  = {2005},

date = {2005-06-01},

journal = {Proteins},

volume = {59},

number = {4},

pages = {869--874},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15848771,

title = {Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF},

author = {Youhoon Chong and Inkyu Hwang and Ali Tavassoli and Yan Zhang and Ian A Wilson and Stephen J Benkovic and Dale L Boger},

doi = {10.1016/j.bmc.2004.11.050},

issn = {0968-0896},

year  = {2005},

date = {2005-05-01},

journal = {Bioorg Med Chem},

volume = {13},

number = {10},

pages = {3587--3592},

abstract = {Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-DDACTHF (1), which incorporate L-glutamine (2) and L-isoglutamine (3) in place of L-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the L-glutamate alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15848772,

title = {Synthesis and biological evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway},

author = {Heng Cheng and Inkyu Hwang and Youhoon Chong and Ali Tavassoli and Michael E Webb and Yan Zhang and Ian A Wilson and Stephen J Benkovic and Dale L Boger},

doi = {10.1016/j.bmc.2004.11.049},

issn = {0968-0896},

year  = {2005},

date = {2005-05-01},

journal = {Bioorg Med Chem},

volume = {13},

number = {10},

pages = {3593--3599},

abstract = {The synthesis and evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K(i) = 0.50 microM), whereas it was inactive (K(i) > 100 microM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 microM).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15848770,

title = {Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway},

author = {Heng Cheng and Youhoon Chong and Inkyu Hwang and Ali Tavassoli and Yan Zhang and Ian A Wilson and Stephen J Benkovic and Dale L Boger},

doi = {10.1016/j.bmc.2004.12.004},

issn = {0968-0896},

year  = {2005},

date = {2005-05-01},

journal = {Bioorg Med Chem},

volume = {13},

number = {10},

pages = {3577--3585},

abstract = {The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K(i) = 0.23 microM), 10-methanesulfonyl-5-DACTHF (2, K(i) = 0.58 microM), and 10-methylthio-DDACTHF (3, K(i) = 0.25 microM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC50 = 1.0 microM and 2, IC50 = 2.0 microM).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15840835,

title = {Crystal structures of apo wild-type M. jannaschii tyrosyl-tRNA synthetase (TyrRS) and an engineered TyrRS specific for O-methyl-L-tyrosine},

author = {Yan Zhang and Lei Wang and Peter G Schultz and Ian A Wilson},

doi = {10.1110/ps.041239305},

issn = {0961-8368},

year  = {2005},

date = {2005-05-01},

journal = {Protein Sci},

volume = {14},

number = {5},

pages = {1340--1349},

abstract = {The Methanococcus jannaschii tRNA(Tyr)/TyrRS pair has been engineered to incorporate unnatural amino acids into proteins in E. coli. To reveal the structural basis for the altered specificity of mutant TyrRS for O-methyl-L-tyrosine (OMeTyr), the crystal structures for the apo wild-type and mutant M. jannaschii TyrRS were determined at 2.66 and 3.0 A, respectively, for comparison with the published structure of TyrRS complexed with tRNA(Tyr) and substrate tyrosine. A large conformational change was found for the anticodon recognition loop 257-263 of wild-type TyrRS upon tRNA binding in order to facilitate recognition of G34 of the anticodon loop through pi-stacking and hydrogen bonding interactions. Loop 133-143, which is close to the tRNA acceptor stem-binding site, also appears to be stabilized by interaction with the tRNA(Tyr). Binding of the substrate tyrosine results in subtle and cooperative movements of the side chains within the tyrosine-binding pocket. In the OMeTyr-specific mutant synthetase structure, the signature motif KMSKS loop and acceptor stem-binding loop 133-143 were surprisingly ordered in the absence of bound ATP and tRNA. The active-site mutations result in altered hydrogen bonding and steric interactions which favor binding of OMeTyr over L-tyrosine. The structure of the mutant and wild-type TyrRS now provide a basis for generating new active-site libraries to evolve synthetases specific for other unnatural amino acids.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15864273,

title = {Anatomy of CD1-lipid antigen complexes},

author = {D Branch Moody and Dirk M Zajonc and Ian A Wilson},

doi = {10.1038/nri1605},

issn = {1474-1733},

year  = {2005},

date = {2005-05-01},

journal = {Nat Rev Immunol},

volume = {5},

number = {5},

pages = {387--399},

abstract = {CD1 proteins bind lipids to form antigen complexes that contact T-cell receptors and activate T cells. Recent crystal structures of CD1 proteins show that their antigen-binding grooves are composed of up to four pockets (A', C', F' and T') and two antigen portals (C' and F'). Although certain structural features are conserved among CD1 proteins, the grooves of CD1a, CD1b and CD1d differ in the number, shape and connectivity of their antigen-binding pockets. Here, we outline how the portals and pockets of CD1 antigen-binding grooves influence ligand specificity and facilitate the presentation of a surprisingly diverse set of antigenic lipids, glycolipids, lipopeptides and even small, non-lipidic molecules.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15826192,

title = {Kinetic stabilization of an oligomeric protein by a single ligand binding event},

author = {R Luke Wiseman and Steven M Johnson and Matthew S Kelker and Ted Foss and Ian A Wilson and Jeffery W Kelly},

doi = {10.1021/ja042929f},

issn = {0002-7863},

year  = {2005},

date = {2005-04-01},

journal = {J Am Chem Soc},

volume = {127},

number = {15},

pages = {5540--5551},

abstract = {Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (I) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of TTR.I in solution to the exclusion of TTR.I(2) and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K(d1) in nanomolar range and K(d2) in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15769474,

title = {Kinetic stabilization of the native state by protein engineering: implications for inhibition of transthyretin amyloidogenesis},

author = {Ted R Foss and Matthew S Kelker and R Luke Wiseman and Ian A Wilson and Jeffery W Kelly},

doi = {10.1016/j.jmb.2005.01.050},

issn = {0022-2836},

year  = {2005},

date = {2005-04-01},

journal = {J Mol Biol},

volume = {347},

number = {4},

pages = {841--854},

abstract = {The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo rate-limiting dissociation to partially denatured monomers in order to aggregate. TTR contains two distinct quaternary interfaces, one of which defines the binding sites for thyroxine and small-molecule amyloidogenesis inhibitors. Kinetic stabilization of the tetramer can be accomplished either by the binding of amyloidogenesis inhibitors selectively to the native state over the dissociative transition state or by the introduction of trans-suppressor subunits (T119M) into heterotetramers to destabilize the dissociative transition state. In each case, increasing the dissociation activation barrier prevents tetramer dissociation. Herein, we demonstrate that tethering two subunits whose quaternary interface defines the thyroxine binding site also dramatically increases the barrier for tetramer dissociation, apparently by destabilization of the dissociative transition state. The tethered construct (TTR-L-TTR)2 is structurally and functionally equivalent to wild-type TTR. Urea is unable to denature (TTR-L-TTR)2, yet it is able to maintain the denatured state once denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2 is kinetically rather than thermodynamically stabilized, consistent with the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves. Studies focused on a construct containing a single TTR-L-TTR chain and two normal monomer subunits establish that alteration of only one quaternary structural interface is sufficient to impose kinetic stabilization on the entire quaternary structure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15788533,

title = {Structural origins of efficient proton abstraction from carbon by a catalytic antibody},

author = {Erik W Debler and Shuichiro Ito and Florian P Seebeck and Andreas Heine and Donald Hilvert and Ian A Wilson},

doi = {10.1073/pnas.0409207102},

issn = {0027-8424},

year  = {2005},

date = {2005-04-01},

journal = {Proc Natl Acad Sci U S A},

volume = {102},

number = {14},

pages = {4984--4989},

abstract = {Antibody 34E4 catalyzes the conversion of benzisoxazoles to salicylonitriles with high rates and multiple turnovers. The crystal structure of its complex with the benzimidazolium hapten at 2.5-angstroms resolution shows that a combination of hydrogen bonding, pi stacking, and van der Waals interactions is exploited to position both the base, Glu(H50), and the substrate for efficient proton transfer. Suboptimal placement of the catalytic carboxylate, as observed in the 2.8-angstroms structure of the Glu(H50)Asp variant, results in substantially reduced catalytic efficiency. In addition to imposing high positional order on the transition state, the antibody pocket provides a highly structured microenvironment for the reaction in which the carboxylate base is activated through partial desolvation, and the highly polarizable transition state is stabilized by dispersion interactions with the aromatic residue Trp(L91) and solvation of the leaving group oxygen by external water. The enzyme-like efficiency of general base catalysis in this system directly reflects the original hapten design, in which a charged guanidinium moiety was strategically used to elicit an accurately positioned functional group in an appropriate reaction environment and suggests that even larger catalytic effects may be achievable by extending this approach to the induction of acid-base pairs capable of bifunctional catalysis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15657930,

title = {Crystal structure of an alanine-glyoxylate aminotransferase from Anabaena sp. at 1.70 A resolution reveals a noncovalently linked PLP cofactor},

author = {Gye Won Han and Robert Schwarzenbacher and Rebecca Page and Lukasz Jaroszewski and Polat Abdubek and Eileen Ambing and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Justin Haugen and Michael Hornsby and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Inna Levin and Daniel McMullan and Timothy M McPhillips and Mitchell D Miller and Andrew Morse and Kin Moy and Edward Nigoghossian and Jie Ouyang and Jessica Paulsen and Kevin Quijano and Ron Reyes and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Frank von Delft and Xianhong Wang and Bill West and Aprilfawn White and Guenter Wolf and Qingping Xu and Olga Zagnitko and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20360},

issn = {1097-0134},

year  = {2005},

date = {2005-03-01},

journal = {Proteins},

volume = {58},

number = {4},

pages = {971--975},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15651027,

title = {Crystal structure of a formiminotetrahydrofolate cyclodeaminase (TM1560) from Thermotoga maritima at 2.80 A resolution reveals a new fold},

author = {Qingping Xu and Robert Schwarzenbacher and Daniel McMullan and Polat Abdubek and Eileen Ambing and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Eric Hampton and Michael Hornsby and Lukasz Jaroszewski and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Inna Levin and Mitchell D Miller and Andrew Morse and Kin Moy and Jie Ouyang and Rebecca Page and Kevin Quijano and Ron Reyes and Alyssa Robb and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Frank von Delft and Xianhong Wang and Bill West and Aprilfawn White and Guenter Wolf and Olga Zagnitko and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20364},

issn = {1097-0134},

year  = {2005},

date = {2005-03-01},

journal = {Proteins},

volume = {58},

number = {4},

pages = {976--981},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15624212,

title = {Crystal structure of an alpha/beta serine hydrolase (YDR428C) from Saccharomyces cerevisiae at 1.85 A resolution},

author = {Joseph W Arndt and Robert Schwarzenbacher and Rebecca Page and Polat Abdubek and Eileen Ambing and Tanya Biorac and Jaume M Canaves and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Michael DiDonato and Marc-André Elsliger and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Joanna Hale and Eric Hampton and Gye Won Han and Justin Haugen and Michael Hornsby and Heath E Klock and Eric Koesema and Andreas Kreusch and Peter Kuhn and Lukasz Jaroszewski and Scott A Lesley and Inna Levin and Daniel McMullan and Timothy M McPhillips and Mitchell D Miller and Andrew Morse and Kin Moy and Edward Nigoghossian and Jie Ouyang and Wolfgang S Peti and Kevin Quijano and Ron Reyes and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Frank von Delft and Xianhong Wang and Bill West and Aprilfawn White and Guenter Wolf and Qingping Xu and Olga Zagnitko and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20336},

issn = {1097-0134},

year  = {2005},

date = {2005-02-01},

journal = {Proteins},

volume = {58},

number = {3},

pages = {755--758},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15677718,

title = {NMR screening and crystal quality of bacterially expressed prokaryotic and eukaryotic proteins in a structural genomics pipeline},

author = {Rebecca Page and Wolfgang Peti and Ian A Wilson and Raymond C Stevens and Kurt Wüthrich},

doi = {10.1073/pnas.0408490102},

issn = {0027-8424},

year  = {2005},

date = {2005-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {102},

number = {6},

pages = {1901--1905},

abstract = {In the Joint Center for Structural Genomics, one-dimensional (1D) 1H NMR spectroscopy is routinely used to characterize the folded state of protein targets and, thus, serves to guide subsequent crystallization efforts and to identify proteins for NMR structure determination. Here, we describe 1D 1H NMR screening of a group of 79 mouse homologue proteins, which correlates the NMR data with the outcome of subsequent crystallization experiments and crystallographic structure determination. Based on the 1D 1H NMR spectra, the proteins are classified into four groups, "A" to "D." A-type proteins are candidates for structure determination by NMR or crystallography; "B"-type are earmarked for crystallography; "C" indicates folded globular proteins with broadened line shapes; and "D" are nonglobular, "unfolded" polypeptides. The results obtained from coarse- and fine-screen crystallization trials imply that only A- and B-type proteins should be used for extensive crystallization trials in the future, with C and D proteins subjected only to coarse-screen crystallization trials. Of the presently studied 79 soluble protein targets, 63% yielded A- or B-quality 1D 1H NMR spectra. Although similar yields of crystallization hits were obtained for all four groups, A to D, crystals from A- and B-type proteins diffracted on average to significantly higher resolution than crystals produced from C- or D-type proteins. Furthermore, the output of refined crystal structures from this test set of proteins was 4-fold higher for A- and B-type than for C- and D-type proteins.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15653316,

title = {CD1 assembly and the formation of CD1-antigen complexes},

author = {David L Hava and Manfred Brigl and Peter van den Elzen and Dirk M Zajonc and Ian A Wilson and Michael B Brenner},

doi = {10.1016/j.coi.2004.12.003},

issn = {0952-7915},

year  = {2005},

date = {2005-02-01},

journal = {Curr Opin Immunol},

volume = {17},

number = {1},

pages = {88--94},

abstract = {The CD1 antigen presentation system presents lipid antigens to effector T cells, which have diverse roles in antimicrobial responses, antitumor immunity and in regulating the balance between tolerance and autoimmunity. The trafficking of CD1 molecules and lipid antigens facilitates their intersection and binding in specific intracellular compartments. Recent studies have now identified unexpected accessory molecules that are critical to CD1 assembly and lipid loading. The atomic structures of CD1-antigen complexes have defined both the orientation of polar headgroups between the alpha1 and alpha2 helices of CD1 and the manner in which distinct CD1 isoforms bind a range of lipids that have different lengths and numbers of hydrocarbon chains.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15723805,

title = {Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41},

author = {Rosa M F Cardoso and Michael B Zwick and Robyn L Stanfield and Renate Kunert and James M Binley and Hermann Katinger and Dennis R Burton and Ian A Wilson},

doi = {10.1016/j.immuni.2004.12.011},

issn = {1074-7613},

year  = {2005},

date = {2005-02-01},

journal = {Immunity},

volume = {22},

number = {2},

pages = {163--173},

abstract = {Broadly neutralizing monoclonal antibodies to HIV-1 are rare but invaluable for vaccine design. 4E10 is the broadest neutralizing antibody known and recognizes a contiguous and highly conserved epitope in the membrane-proximal region of gp41. The crystal structure of Fab 4E10 was determined at 2.2 A resolution in complex with a 13-residue peptide containing the gp41 core epitope (NWFDIT). The bound peptide adopts a helical conformation in which the key contact residues, TrpP672, PheP673, IleP675, and ThrP676, map to one face of the helix. The peptide binds in a hydrophobic pocket that may emulate its potential interaction with the host cell membrane. The long CDR H3 of the antibody extends beyond the bound peptide in an orientation that suggests that its apex could contact the viral membrane when 4E10 is bound to its membrane-proximal epitope. These structural insights should assist in the design of immunogens to elicit 4E10-like neutralizing responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15723809,

title = {Molecular mechanism of lipopeptide presentation by CD1a},

author = {Dirk M Zajonc and M D Max Crispin and Thomas A Bowden and David C Young and Tan-Yun Cheng and Jingdan Hu and Catherine E Costello and Pauline M Rudd and Raymond A Dwek and Marvin J Miller and Michael B Brenner and D Branch Moody and Ian A Wilson},

doi = {10.1016/j.immuni.2004.12.009},

issn = {1074-7613},

year  = {2005},

date = {2005-02-01},

journal = {Immunity},

volume = {22},

number = {2},

pages = {209--219},

abstract = {CD1a is expressed on Langerhans cells (LCs) and dendritic cells (DCs), where it mediates T cell recognition of glycolipid and lipopeptide antigens that contain either one or two alkyl chains. We demonstrate here that CD1a-restricted T cells can discriminate the peptide component of didehydroxymycobactin lipopeptides. Structure analysis of CD1a cocrystallized with a synthetic mycobactin lipopeptide at 2.8 A resolution further reveals that the single alkyl chain is inserted deep within the A' pocket of the groove, whereas its two peptidic branches protrude along the F' pocket to the outer, alpha-helical surface of CD1a for recognition by the TCR. Remarkably, the cyclized lysine branch of the peptide moiety lies in the shallow F' pocket in a conformation that closely mimics that of the alkyl chain in the CD1a-sulfatide structure. Thus, this structural study illustrates how a single chain lipid can be presented by CD1 and that the peptide moiety of the lipopeptide is recognized by the TCR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16211502,

title = {Protein production and crystallization at the joint center for structural genomics},

author = {Scott A Lesley and Ian A Wilson},

doi = {10.1007/s10969-005-2897-2},

issn = {1345-711X},

year  = {2005},

date = {2005-01-01},

journal = {J Struct Funct Genomics},

volume = {6},

number = {2-3},

pages = {71--79},

abstract = {By definition, structural genomics centers must be able to address a large number of diverse protein targets. The methods developed should permit parallel and cost-effective processing while allowing for the diverse nature of proteins. Our approach to this problem is a multi-tiered effort where targets are characterized and categorized by behavior and processed in parallel by appropriate methods. The Joint Center for Structural Genomics (JCSG) has applied this tactic to create a fully integrated and scaleable structure determination pipeline. Highlights of the development of the current pipeline for protein production and crystallization are presented here.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16400808,

title = {Glycosylation and the function of the T cell co-receptor CD8},

author = {David A Shore and Ian A Wilson and Raymond A Dwek and Pauline M Rudd},

doi = {10.1007/0-387-25515-X_12},

issn = {0065-2598},

year  = {2005},

date = {2005-01-01},

journal = {Adv Exp Med Biol},

volume = {564},

pages = {71--84},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16720977,

title = {Structural studies of human HIV-1 V3 antibodies},

author = {Robyn L Stanfield and Ian A Wilson},

issn = {1093-2607},

year  = {2005},

date = {2005-01-01},

journal = {Hum Antibodies},

volume = {14},

number = {3-4},

pages = {73--80},

abstract = {X-ray crystallographic structures of two human, anti-V3 HIV-1 neutralizing antibodies, 447-52D and 2219, show how the two antibodies use different strategies for their cross-reactivity with different V3 sequences. 447-52D recognizes V3 primarily through main-chain hydrogen bonds to the N-terminal side of V3, with the GPGR tip region buried in the antigen-combining site. The side chains on the N-terminal side of V3 are exposed to solvent, allowing for sequence changes in this region, thus explaining how 447-52D can neutralize a wide array of viral isolates. Antibody 2219 contacts a more extensive V3 surface, with more side-chain involvement. However, residues at the GPGR tip are exposed to solvent, with no constraints on residue size, so that binding to unusual tip sequences with larger side chains such as RPRQ is possible.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15615517,

title = {Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors},

author = {Chenglong Li and Lan Xu and Dennis W Wolan and Ian A Wilson and Arthur J Olson},

doi = {10.1021/jm049504o},

issn = {0022-2623},

year  = {2004},

date = {2004-12-01},

journal = {J Med Chem},

volume = {47},

number = {27},

pages = {6681--6690},

abstract = {AICAR transformylase (5-aminoimidazole-4-carboxamide ribonucleotide transformylase) is a folate-dependent activity of the bifunctional protein ATIC (AICAR transformylase and IMP cyclohydrolase) and is responsible for catalyzing the penultimate step of the de novo purine biosynthetic pathway. As such, AICAR transformylase has been proposed as a potential target for antineoplastic drug design. Virtual screening of the human AICAR transformylase active site by use of AutoDock against the NCI diversity set, a library of compounds with nonredundant pharmacophore profiles, has revealed 44 potential inhibitor candidates. In vitro inhibition assay of 16 soluble compounds from this list revealed that eight compounds with novel scaffolds, relative to the general folate template, had micromolar inhibition. Subsequent extension of docking trials on compounds with similar scaffolds from the entire NCI-3D database has unveiled 11 additional inhibitors that were confirmed by the in vitro inhibition assay. In particular, one compound, NSC30171, had nanomolar inhibition (K(i) = 154 nM, IC(50) = 600 nM) against AICAR transformylase. These 19 inhibitors serve as novel templates/scaffolds for development of more potent and specific non-folate-based AICAR transformylase inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15561137,

title = {Crystal structure of mouse triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.76 A},

author = {Matthew S Kelker and Erik W Debler and Ian A Wilson},

doi = {10.1016/j.jmb.2004.10.009},

issn = {0022-2836},

year  = {2004},

date = {2004-12-01},

journal = {J Mol Biol},

volume = {344},

number = {5},

pages = {1175--1181},

abstract = {Triggering receptor expressed on myeloid cells (TREM) 1 is an activating receptor expressed on myeloid cells whose ligand(s) remain elusive. TREM-1 stimulation activates neutrophils and monocytes and induces the secretion of pro-inflammatory molecules, which amplifies the Toll-like receptor-initiated responses to invading pathogens. In addition, TREM-1 mediates the septic shock pathway, and thus represents a potential therapeutic target. We report the crystal structure of the mouse TREM-1 extracellular domain at 1.76A resolution. The mouse extracellular domain is monomeric, consistent with our previous human TREM-1 structure, and strongly supports the contention that the globular TREM-1 head is a monomer contrary to proposals of a symmetric dimer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15563589,

title = {Printed covalent glycan array for ligand profiling of diverse glycan binding proteins},

author = {Ola Blixt and Steve Head and Tony Mondala and Christopher Scanlan and Margaret E Huflejt and Richard Alvarez and Marian C Bryan and Fabio Fazio and Daniel Calarese and James Stevens and Nahid Razi and David J Stevens and John J Skehel and Irma van Die and Dennis R Burton and Ian A Wilson and Richard Cummings and Nicolai Bovin and Chi-Huey Wong and James C Paulson},

doi = {10.1073/pnas.0407902101},

issn = {0027-8424},

year  = {2004},

date = {2004-12-01},

journal = {Proc Natl Acad Sci U S A},

volume = {101},

number = {49},

pages = {17033--17038},

abstract = {Here we describe a glycan microarray constructed by using standard robotic microarray printing technology to couple amine functionalized glycans to an amino-reactive glass slide. The array comprises 200 synthetic and natural glycan sequences representing major glycan structures of glycoproteins and glycolipids. The array has remarkable utility for profiling the specificity of a diverse range of glycan binding proteins, including C-type lectins, siglecs, galectins, anticarbohydrate antibodies, lectins from plants and microbes, and intact viruses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15544807,

title = {Protein biophysical properties that correlate with crystallization success in Thermotoga maritima: maximum clustering strategy for structural genomics},

author = {Jaume M Canaves and Rebecca Page and Ian A Wilson and Raymond C Stevens},

doi = {10.1016/j.jmb.2004.09.076},

issn = {0022-2836},

year  = {2004},

date = {2004-12-01},

journal = {J Mol Biol},

volume = {344},

number = {4},

pages = {977--991},

abstract = {Cost and time reduction are two of the driving forces in the development of new strategies for protein crystallization and subsequent structure determination. Here, we report the analysis of the Thermotoga maritima proteome, in which we compare the proteins that were successfully expressed, purified and crystallized versus the rest of the proteome. This set of almost 500 proteins represents one of the largest, internally consistent, protein expression and crystallization datasets available. The analysis shows that individual parameters, such as isoelectric point, sequence length, average hydropathy, low complexity regions (SEG), and combinations of these biophysical properties for crystallized proteins define a distinct subset of the T. maritima proteome. The distribution profiles of the various biophysical properties in the expression/crystallization set are then used to extract rules to improve target selection and improve the efficiency and output of structural genomics, as well as general structural biology efforts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15557262,

title = {On the use of DXMS to produce more crystallizable proteins: structures of the T. maritima proteins TM0160 and TM1171},

author = {Glen Spraggon and Dennis Pantazatos and Heath E Klock and Ian A Wilson and Virgil L Woods and Scott A Lesley},

doi = {10.1110/ps.04939904},

issn = {0961-8368},

year  = {2004},

date = {2004-12-01},

journal = {Protein Sci},

volume = {13},

number = {12},

pages = {3187--3199},

abstract = {The structure of two Thermotoga maritima proteins, a conserved hypothetical protein (TM0160) and a transcriptional regulator (TM1171), have now been determined at 1.9 A and 2.3 A resolution, respectively, as part of a large-scale structural genomics project. Our first efforts to crystallize full-length versions of these targets were unsuccessful. However, analysis of the recombinant purified proteins using the technique of enhanced amide hydrogen/deuterium exchange mass spectroscopy (DXMS) revealed substantial regions of rapid amide deuterium hydrogen exchange, consistent with flexible regions of the structures. Based on these exchange data, truncations were designed to selectively remove the disordered C-terminal regions, and the resulting daughter proteins showed greatly enhanced crystallizability. Comparative DXMS analysis of full-length protein versus truncated forms demonstrated complete and exact preservation of the exchange rate profiles in the retained sequence, indicative of conservation of the native folded structure. This study presents the first structures produced with the aid of the DXMS method for salvaging intractable crystallization targets. The structure of TM0160 represents a new fold and highlights the use of this approach where any prior structural knowledge is absent. The structure of TM1171 represents an example where the lack of a substrate/cofactor may impair crystallization. The details of both structures are presented and discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15355974,

title = {Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening},

author = {Lan Xu and Chenglong Li and Arthur J Olson and Ian A Wilson},

doi = {10.1074/jbc.M406801200},

issn = {0021-9258},

year  = {2004},

date = {2004-11-01},

journal = {J Biol Chem},

volume = {279},

number = {48},

pages = {50555--50565},

abstract = {Aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase), one of the two folate-dependent enzymes in the de novo purine biosynthesis pathway, is a promising target for anti-neoplastic chemotherapy. Although classic antifolates, such as methotrexate, have been developed as anticancer agents, their general toxicity and drug resistance are major issues associated with their clinical use and future development. Identification of inhibitors with novel scaffolds could be an attractive alternative. We present here the crystal structure of avian AICAR Tfase complexed with the first non-folate based inhibitor identified through virtual ligand screening of the National Cancer Institute Diversity Set. The inhibitor 326203-A (2-[5-hydroxy-3-methyl-1-(2-methyl-4-sulfophenyl)-1H-pyrazol-4-ylazo]-4-sulfo-benzoic acid) displayed competitive inhibition against the natural cofactor, 10-formyl-tetrahydrofolate, with a K(i) of 7.1 mum. The crystal structure of AICAR Tfase with 326203-A at 1.8 A resolution revealed a unique binding mode compared with antifolate inhibitors. The inhibitor also accessed an additional binding pocket that is not occupied by antifolates. The sulfonate group of 326203-A appears to form the dominant interaction of the inhibitor with the proposed oxyanion hole through interaction with a helix dipole and Lys(267). An aromatic interaction with Phe(316) also likely contributes to favorable binding. Based on these structural insights, several inhibitors with improved potency were subsequently identified in the National Cancer Institute Compound Library and the Available Chemical Directory by similarity search and molecular modeling methods. These results provide further support for our combined virtual ligand screening rational design approach for the discovery of novel, non-folate-based inhibitors of AICAR Tfase.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15491612,

title = {The origin of enantioselectivity in aldolase antibodies: crystal structure, site-directed mutagenesis, and computational analysis},

author = {Xueyong Zhu and Fujie Tanaka and Yunfeng Hu and Andreas Heine and Roberta Fuller and Guofu Zhong and Arthur J Olson and Richard A Lerner and Carlos F Barbas and Ian A Wilson},

doi = {10.1016/j.jmb.2004.08.102},

issn = {0022-2836},

year  = {2004},

date = {2004-11-01},

journal = {J Mol Biol},

volume = {343},

number = {5},

pages = {1269--1280},

abstract = {Catalytic aldolase antibodies, generated by reactive immunization, catalyze the aldol reaction with the efficiency of natural enzymes, but accept a much broader range of substrates. Two separate groups of aldolase antibodies that catalyze the same aldol reactions with antipodal selectivity were analyzed by comparing their amino acid sequences with their crystal structures, site-directed mutagenesis data, and computational docking of the transition states of the aldol reaction. The crystal structure of aldolase antibody 93F3 Fab' at 2.5A resolution revealed a combining site with two lysine residues, including LysL89 that reacts to form the covalent enamine intermediate. In contrast, antibody 33F12 has one active site lysine, LysH93. The reactive lysine residues in each group of antibodies are differentially located on the heavy and light chain variable regions in pseudo-symmetric opposite orientations, but both within highly hydrophobic environments. Thus, the defining feature for the observed enantioselectivities of these aldolase antibody catalysts is the respective location and relative disposition of the reactive lysine residues within the active sites of these catalysts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15542540,

title = {Improved design of an antigen with enhanced specificity for the broadly HIV-neutralizing antibody b12},

author = {R Pantophlet and I A Wilson and D R Burton},

doi = {10.1093/protein/gzh085},

issn = {1741-0126},

year  = {2004},

date = {2004-10-01},

journal = {Protein Eng Des Sel},

volume = {17},

number = {10},

pages = {749--758},

abstract = {In an attempt to design immunogens that elicit broadly HIV-neutralizing antibodies, we recently engineered monomeric HIV-1 gp120 to bind preferentially b12, a broadly neutralizing antibody to the CD4-binding site (CD4bs) on gp120, by mutating four central residues in the CD4bs to alanine and introducing extra N-glycosylation sites potentially to mask unwanted B-cell epitopes. Despite the favorable antigenicity of this mutant, it harbors two potential caveats that may limit its effectiveness to elicit b12-like antibodies: (i) b12-binding affinity is reduced relative to wild-type gp120 and (ii) binding of some non-neutralizing antibodies to the N-terminal C1 region of gp120 is still observed. Here, we sought to correct these potential limitations. By reverting one of the added N-glycosylation sites on the gp120 core, b12 binding was improved without affecting the epitope-masking properties of the original mutant. Furthermore, truncation of the gp120 N-terminus eliminated binding of the anti-C1 antibodies. Finally, based on the binding profiles of additional non-neutralizing antibodies tested here, further N-glycosylation sites were incorporated to mask their corresponding epitopes. The resulting hyperglycosylated gp120 variants bind b12 and another broadly neutralizing antibody, 2G12, with apparent affinities approaching that of wild-type gp120, but do not bind 21 non- or weakly neutralizing antibodies to seven different epitopes on gp120. These hyperglycosylated variants expand our panel of glycoengineered gp120s that are currently being evaluated for their ability to elicit broadly neutralizing antibodies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15476818,

title = {Analysis of the class I aldolase binding site architecture based on the crystal structure of 2-deoxyribose-5-phosphate aldolase at 0.99A resolution},

author = {Andreas Heine and John G Luz and Chi-Huey Wong and Ian A Wilson},

doi = {10.1016/j.jmb.2004.08.066},

issn = {0022-2836},

year  = {2004},

date = {2004-10-01},

journal = {J Mol Biol},

volume = {343},

number = {4},

pages = {1019--1034},

abstract = {The crystal structure of the bacterial (Escherichia coli) class I 2-deoxyribose-5-phosphate aldolase (DERA) has been determined by Se-Met multiple anomalous dispersion (MAD) methods at 0.99A resolution. This structure represents the highest-resolution X-ray structure of an aldolase determined to date and enables a true atomic view of the enzyme. The crystal structure shows the ubiquitous TIM alpha/beta barrel fold. The enzyme contains two lysine residues in the active site. Lys167 forms the Schiff base intermediate, whereas Lys201, which is in close vicinity to the reactive lysine residue, is responsible for the perturbed pK(a) of Lys167 and, hence, also a key residue in the reaction mechanism. DERA is the only known aldolase that is able to use aldehydes as both aldol donor and acceptor molecules in the aldol reaction and is, therefore, of particular interest as a biocatalyst in synthetic organic chemistry. The uncomplexed DERA structure enables a detailed comparison with the substrate complexes and highlights a conformational change in the phosphate-binding site. Knowledge of the enzyme active-site environment has been the basis for exploration of catalysis of non-natural substrates and of mutagenesis of the phosphate-binding site to expand substrate specificity. Detailed comparison with other class I aldolase enzymes and DERA enzymes from different organisms reveals a similar geometric arrangement of key residues and implies a potential role for water as a general base in the catalytic mechanism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15479737,

title = {COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code},

author = {Xiaodong Wang and Jeanne Matteson and Yu An and Bryan Moyer and Jin-San Yoo and Sergei Bannykh and Ian A Wilson and John R Riordan and William E Balch},

doi = {10.1083/jcb.200401035},

issn = {0021-9525},

year  = {2004},

date = {2004-10-01},

journal = {J Cell Biol},

volume = {167},

number = {1},

pages = {65--74},

abstract = {Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) DeltaF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in DeltaF508-expressing patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15326606,

title = {Crystal structure of a tandem cystathionine-beta-synthase (CBS) domain protein (TM0935) from Thermotoga maritima at 1.87 A resolution},

author = {Mitchell D Miller and Robert Schwarzenbacher and Frank von Delft and Polat Abdubek and Eileen Ambing and Tanya Biorac and Linda S Brinen and Jaume M Canaves and Jamison Cambell and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Mike DiDonato and Marc-André Elsliger and Said Eshagi and Ross Floyd and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Eric Hampton and Lukasz Jaroszewski and Cathy Karlak and Heath E Klock and Eric Koesema and John S Kovarik and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Inna Levin and Daniel McMullan and Timothy M McPhillips and Andrew Morse and Kin Moy and Jie Ouyang and Rebecca Page and Kevin Quijano and Alyssa Robb and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Xianhong Wang and Bill West and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20024},

issn = {1097-0134},

year  = {2004},

date = {2004-10-01},

journal = {Proteins},

volume = {57},

number = {1},

pages = {213--217},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15351648,

title = {Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.47 A},

author = {Matthew S Kelker and Theodore R Foss and Wolfgang Peti and Luc Teyton and Jeffrey W Kelly and Kurt Wüthrich and Ian A Wilson},

doi = {10.1016/j.jmb.2004.07.089},

issn = {0022-2836},

year  = {2004},

date = {2004-09-01},

journal = {J Mol Biol},

volume = {342},

number = {4},

pages = {1237--1248},

abstract = {The triggering receptor expressed on myeloid cells (TREM) family of single extracellular immunoglobulin receptors includes both activating and inhibitory isoforms whose ligands are unknown. TREM-1 activation amplifies the Toll-like receptor initiated responses to invading pathogens allowing the secretion of pro-inflammatory chemokines and cytokines. Hence, TREM-1 amplifies the inflammation induced by both bacteria and fungi, and thus represents a potential therapeutic target. We report the crystal structure of the human TREM-1 extracellular domain at 1.47 A resolution. The overall fold places it within the V-type immunoglobulin domain family and reveals close homology with Ig domains from antibodies, T-cell receptors and other activating receptors, such as NKp44. With the additional use of analytical ultracentrifugation and 1H NMR spectroscopy of both human and mouse TREM-1, we have conclusively demonstrated the monomeric state of this extracellular ectodomain in solution and, presumably, of the TREM family in general.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15319492,

title = {Crystal structure of a shark single-domain antibody V region in complex with lysozyme},

author = {Robyn L Stanfield and Helen Dooley and Martin F Flajnik and Ian A Wilson},

doi = {10.1126/science.1101148},

issn = {1095-9203},

year  = {2004},

date = {2004-09-01},

journal = {Science},

volume = {305},

number = {5691},

pages = {1770--1773},

abstract = {Cartilaginous fish are the phylogenetically oldest living organisms known to possess components of the vertebrate adaptive immune system. Key to their immune response are heavy-chain, homodimeric immunoglobulins called new antigen receptors (IgNARs), in which the variable (V) domains recognize antigens with only a single immunoglobulin domain, akin to camelid heavy-chain V domains. The 1.45 angstrom resolution crystal structure of the type I IgNAR V domain in complex with hen egg-white lysozyme (HEL) reveals a minimal antigen-binding domain that contains only two of the three conventional complementarity-determining regions but still binds HEL with nanomolar affinity by means of a binding interface comparable in size to conventional antibodies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15229893,

title = {Crystal structure of a novel manganese-containing cupin (TM1459) from Thermotoga maritima at 1.65 A resolution},

author = {Lukasz Jaroszewski and Robert Schwarzenbacher and Frank von Delft and Daniel McMullan and Linda S Brinen and Jaume M Canaves and Xiaoping Dai and Ashley M Deacon and Mike DiDonato and Marc-André Elsliger and Said Eshagi and Ross Floyd and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Eric Hampton and Inna Levin and Cathy Karlak and Heath E Klock and Eric Koesema and John S Kovarik and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Timothy M McPhillips and Mitchell D Miller and Andrew Morse and Kin Moy and Jie Ouyang and Rebecca Page and Kevin Quijano and Ron Reyes and Fred Rezezadeh and Alyssa Robb and Eric Sims and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Xianhong Wang and Bill West and Guenter Wolf and Qingping Xu and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20130},

issn = {1097-0134},

year  = {2004},

date = {2004-08-01},

journal = {Proteins},

volume = {56},

number = {3},

pages = {611--614},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15229895,

title = {Crystal structure of an allantoicase (YIR029W) from Saccharomyces cerevisiae at 2.4 A resolution},

author = {Qingping Xu and Robert Schwarzenbacher and Rebecca Page and Eric Sims and Polat Abdubek and Eileen Ambing and Tanya Biorac and Linda S Brinen and Jamison Cambell and Jaume M Canaves and Hsiu-Ju Chiu and Xiaoping Dai and Ashley M Deacon and Mike DiDonato and Marc-André Elsliger and Ross Floyd and Adam Godzik and Carina Grittini and Slawomir K Grzechnik and Eric Hampton and Lukasz Jaroszewski and Cathy Karlak and Heath E Klock and Eric Koesema and John S Kovarik and Andreas Kreusch and Peter Kuhn and Scott A Lesley and Inna Levin and Daniel McMullan and Timothy M McPhillips and Mitchell D Miller and Andrew Morse and Kin Moy and Jie Ouyang and Kevin Quijano and Ron Reyes and Fred Rezezadeh and Alyssa Robb and Glen Spraggon and Raymond C Stevens and Henry van den Bedem and Jeff Velasquez and Juli Vincent and Frank von Delft and Xianhong Wang and Bill West and Guenter Wolf and Keith O Hodgson and John Wooley and Ian A Wilson},

doi = {10.1002/prot.20164},

issn = {1097-0134},

year  = {2004},

date = {2004-08-01},

journal = {Proteins},

volume = {56},

number = {3},

pages = {619--624},

keywords = {},

pubstate = {published},

tppubtype = {article}

}