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Science 27 June 2003:
Vol. 300. no. 5628, pp. 2065 - 2071
DOI: 10.1126/science.1083182
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Research Articles

Antibody Domain Exchange Is an Immunological Solution to Carbohydrate Cluster Recognition

Daniel A. Calarese,1 Christopher N. Scanlan,2,5 Michael B. Zwick,2 Songpon Deechongkit,3 Yusuke Mimura,5 Renate Kunert,6 Ping Zhu,7 Mark R. Wormald,5 Robyn L. Stanfield,1 Kenneth H. Roux,7 Jeffery W. Kelly,3,4 Pauline M. Rudd,5 Raymond A. Dwek,5 Hermann Katinger,6 Dennis R. Burton,1,2* Ian A. Wilson1,4*

Human antibody 2G12 neutralizes a broad range of human immunodeficiency virus type 1 (HIV-1) isolates by binding an unusually dense cluster of carbohydrate moieties on the "silent" face of the gp120 envelope glycoprotein. Crystal structures of Fab 2G12 and its complexes with the disaccharide Man{alpha}1-2Man and with the oligosaccharide Man9GlcNAc2 revealed that two Fabs assemble into an interlocked VH domain-swapped dimer. Further biochemical, biophysical, and mutagenesis data strongly support a Fab-dimerized antibody as the prevalent form that recognizes gp120. The extraordinary configuration of this antibody provides an extended surface, with newly described binding sites, for multivalent interaction with a conserved cluster of oligomannose type sugars on the surface of gp120. The unique interdigitation of Fab domains within an antibody uncovers a previously unappreciated mechanism for high-affinity recognition of carbohydrate or other repeating epitopes on cell or microbial surfaces.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
5 The Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
6 Institute for Applied Microbiology, University of Agriculture, Vienna, Austria.
7 Department of Biological Science and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.

* To whom correspondence should be addressed. E-mail: burton{at}scripps.edu, wilson{at}scripps.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Glycoconjugate Antigen Based on the Recognition Motif of a Broadly Neutralizing Human Immunodeficiency Virus Antibody, 2G12, Is Immunogenic but Elicits Antibodies Unable To Bind to the Self Glycans of gp120.
R. D. Astronomo, H.-K. Lee, C. N. Scanlan, R. Pantophlet, C.-Y. Huang, I. A. Wilson, O. Blixt, R. A. Dwek, C.-H. Wong, and D. R. Burton (2008)
J. Virol. 82, 6359-6368
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An Engineered Saccharomyces cerevisiae Strain Binds the Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody 2G12 and Elicits Mannose-Specific gp120-Binding Antibodies.
R. J. Luallen, J. Lin, H. Fu, K. K. Cai, C. Agrawal, I. Mboudjeka, F.-H. Lee, D. Montefiori, D. F. Smith, R. W. Doms, et al. (2008)
J. Virol. 82, 6447-6457
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Breast Cancer Diagnosis and Prognosis through Quantitative Measurements of Serum Glycan Profiles.
Z. Kyselova, Y. Mechref, P. Kang, J. A. Goetz, L. E. Dobrolecki, G. W. Sledge, L. Schnaper, R. J. Hickey, L. H. Malkas, and M. V. Novotny (2008)
Clin. Chem. 54, 1166-1175
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A peptide inhibitor of HIV-1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120.
A. Menendez, D. A. Calarese, R. L. Stanfield, K. C. Chow, C. N. Scanlan, R. Kunert, H. Katinger, D. R. Burton, I. A. Wilson, and J. K. Scott (2008)
FASEB J 22, 1380-1392
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Identification of an N-Linked Glycosylation in the C4 Region of HIV-1 Envelope gp120 That Is Critical for Recognition of Neighboring CD4 T Cell Epitopes.
H. Li, P. C. Chien Jr., M. Tuen, M. L. Visciano, S. Cohen, S. Blais, C.-F. Xu, H.-T. Zhang, and C. E. Hioe (2008)
J. Immunol. 180, 4011-4021
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Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN.
S.-K. Wang, P.-H. Liang, R. D. Astronomo, T.-L. Hsu, S.-L. Hsieh, D. R. Burton, and C.-H. Wong (2008)
PNAS 105, 3690-3695
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The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design.
M. Montero, N. E. van Houten, X. Wang, and J. K. Scott (2008)
Microbiol. Mol. Biol. Rev. 72, 54-84
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A plant-derived human monoclonal antibody induces an anti-carbohydrate immune response in rabbits.
C. Jin, F. Altmann, R. Strasser, L. Mach, M. Schahs, R. Kunert, T. Rademacher, J. Glossl, and H. Steinkellner (2008)
Glycobiology 18, 235-241
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N-Linked Glycan Modifications in gp120 of Human Immunodeficiency Virus Type 1 Subtype C Render Partial Sensitivity to 2G12 Antibody Neutralization.
E. S. Gray, P. L. Moore, R. A. Pantophlet, and L. Morris (2007)
J. Virol. 81, 10769-10776
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Susceptibility of Recently Transmitted Subtype B Human Immunodeficiency Virus Type 1 Variants to Broadly Neutralizing Antibodies.
E. D. Quakkelaar, F. P. J. van Alphen, B. D. M. Boeser-Nunnink, A. C. van Nuenen, R. Pantophlet, and H. Schuitemaker (2007)
J. Virol. 81, 8533-8542
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Identification of the Optimal DC-SIGN Binding Site on Human Immunodeficiency Virus Type 1 gp120.
P. W.-P. Hong, S. Nguyen, S. Young, S. V. Su, and B. Lee (2007)
J. Virol. 81, 8325-8336
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Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors.
A. K. Dhillon, H. Donners, R. Pantophlet, W. E. Johnson, J. M. Decker, G. M. Shaw, F.-H. Lee, D. D. Richman, R. W. Doms, G. Vanham, et al. (2007)
J. Virol. 81, 6548-6562
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Strict specificity for high-mannose type N-glycans and primary structure of a red alga Eucheuma serra lectin.
K. Hori, Y. Sato, K. Ito, Y. Fujiwara, Y. Iwamoto, H. Makino, and A. Kawakubo (2007)
Glycobiology 17, 479-491
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Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy.
M. Law, R. M. F. Cardoso, I. A. Wilson, and D. R. Burton (2007)
J. Virol. 81, 4272-4285
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Time Frames for Neutralization during the Human Immunodeficiency Virus Type 1 Entry Phase, as Monitored in Synchronously Infected Cell Cultures.
H. Haim, I. Steiner, and A. Panet (2007)
J. Virol. 81, 3525-3534
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Solid phase immunoadsorption for therapeutic and analytical studies on neuropathy-associated anti-GM1 antibodies.
K. Townson, J. Boffey, D. Nicholl, J. Veitch, D. Bundle, P. Zhang, E. Samain, T. Antoine, A. Bernardi, D. Arosio, et al. (2007)
Glycobiology 17, 294-303
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Multiple Modes of Binding Enhance the Affinity of DC-SIGN for High Mannose N-Linked Glycans Found on Viral Glycoproteins.
H. Feinberg, R. Castelli, K. Drickamer, P. H. Seeberger, and W. I. Weis (2007)
J. Biol. Chem. 282, 4202-4209
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Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence.
W. J. Honnen, C. Krachmarov, S. C. Kayman, M. K. Gorny, S. Zolla-Pazner, and A. Pinter (2007)
J. Virol. 81, 1424-1432
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Antigen selection from an HIV-1 immune antibody library displayed on yeast yields many novel antibodies compared to selection from the same library displayed on phage.
D.R. Bowley, A.F. Labrijn, M.B. Zwick, and D.R. Burton (2007)
Protein Eng. Des. Sel. 20, 81-90
   Abstract »    Full Text »    PDF »
Pradimicin A, a Carbohydrate-Binding Nonpeptidic Lead Compound for Treatment of Infections with Viruses with Highly Glycosylated Envelopes, Such as Human Immunodeficiency Virus.
J. Balzarini, K. Van Laethem, D. Daelemans, S. Hatse, A. Bugatti, M. Rusnati, Y. Igarashi, T. Oki, and D. Schols (2007)
J. Virol. 81, 362-373
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Genetic and Neutralization Properties of Subtype C Human Immunodeficiency Virus Type 1 Molecular env Clones from Acute and Early Heterosexually Acquired Infections in Southern Africa.
M. Li, J. F. Salazar-Gonzalez, C. A. Derdeyn, L. Morris, C. Williamson, J. E. Robinson, J. M. Decker, Y. Li, M. G. Salazar, V. R. Polonis, et al. (2006)
J. Virol. 80, 11776-11790
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Mutational Pathways, Resistance Profile, and Side Effects of Cyanovirin Relative to Human Immunodeficiency Virus Type 1 Strains with N-Glycan Deletions in Their gp120 Envelopes..
J. Balzarini, K. Van Laethem, W. J. Peumans, E. J. M. Van Damme, A. Bolmstedt, F. Gago, and D. Schols (2006)
J. Virol. 80, 8411-8421
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Crystal Structures of Human Immunodeficiency Virus Type 1 (HIV-1) Neutralizing Antibody 2219 in Complex with Three Different V3 Peptides Reveal a New Binding Mode for HIV-1 Cross-Reactivity..
R. L. Stanfield, M. K. Gorny, S. Zolla-Pazner, and I. A. Wilson (2006)
J. Virol. 80, 6093-6105
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Evidence for a Domain-Swapped CD4 Dimer as the Coreceptor for Binding to Class II MHC..
A. Maekawa, B. Schmidt, B. Fazekas de St. Groth, Y.-H. Sanejouand, and P. J. Hogg (2006)
J. Immunol. 176, 6873-6878
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Nature of Nonfunctional Envelope Proteins on the Surface of Human Immunodeficiency Virus Type 1.
P. L. Moore, E. T. Crooks, L. Porter, P. Zhu, C. S. Cayanan, H. Grise, P. Corcoran, M. B. Zwick, M. Franti, L. Morris, et al. (2006)
J. Virol. 80, 2515-2528
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Carbohydrate-binding Agents Cause Deletions of Highly Conserved Glycosylation Sites in HIV GP120: A NEW THERAPEUTIC CONCEPT TO HIT THE ACHILLES HEEL OF HIV.
J. Balzarini, K. Van Laethem, S. Hatse, M. Froeyen, W. Peumans, E. Van Damme, and D. Schols (2005)
J. Biol. Chem. 280, 41005-41014
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Antibody vs. HIV in a clash of evolutionary titans.
D. R. Burton, R. L. Stanfield, and I. A. Wilson (2005)
PNAS 102, 14943-14948
   Abstract »    Full Text »    PDF »
Interfacial metal and antibody recognition.
T. Zhou, D. H. Hamer, W. A. Hendrickson, Q. J. Sattentau, and P. D. Kwong (2005)
PNAS 102, 14575-14580
   Abstract »    Full Text »    PDF »
Comparing Antigenicity and Immunogenicity of Engineered gp120.
S. Selvarajah, B. Puffer, R. Pantophlet, M. Law, R. W. Doms, and D. R. Burton (2005)
J. Virol. 79, 12148-12163
   Abstract »    Full Text »    PDF »
Concanavalin A binding to HIV envelope protein is less sensitive to mutations in glycosylation sites than monoclonal antibody 2G12.
A. Pashov, S. MacLeod, R. Saha, M. Perry, T. C. VanCott, and T. Kieber-Emmons (2005)
Glycobiology 15, 994-1001
   Abstract »    Full Text »    PDF »
Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12.
D. A. Calarese, H.-K. Lee, C.-Y. Huang, M. D. Best, R. D. Astronomo, R. L. Stanfield, H. Katinger, D. R. Burton, C.-H. Wong, and I. A. Wilson (2005)
PNAS 102, 13372-13377
   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies.
M. Li, F. Gao, J. R. Mascola, L. Stamatatos, V. R. Polonis, M. Koutsoukos, G. Voss, P. Goepfert, P. Gilbert, K. M. Greene, et al. (2005)
J. Virol. 79, 10108-10125
   Abstract »    Full Text »    PDF »
Antigenic Properties of Peptide Mimotopes of HIV-1-associated Carbohydrate Antigens.
A. Pashov, G. Canziani, B. Monzavi-Karbassi, S. V. Kaveri, S. MacLeod, R. Saha, M. Perry, T. C. VanCott, and T. Kieber-Emmons (2005)
J. Biol. Chem. 280, 28959-28965
   Abstract »    Full Text »    PDF »
Crystal Structures of the HIV-1 Inhibitory Cyanobacterial Protein MVL Free and Bound to Man3GlcNAc2: STRUCTURAL BASIS FOR SPECIFICITY AND HIGH-AFFINITY BINDING TO THE CORE PENTASACCHARIDE FROM N-LINKED OLIGOMANNOSIDE.
D. C. Williams Jr., J. Y. Lee, M. Cai, C. A. Bewley, and G. M. Clore (2005)
J. Biol. Chem. 280, 29269-29276
   Abstract »    Full Text »    PDF »
The V1, V2, and V3 Regions of the Human Immunodeficiency Virus Type 1 Envelope Differentially Affect the Viral Phenotype in an Isolate-Dependent Manner.
C. J. Saunders, R. A. McCaffrey, I. Zharkikh, Z. Kraft, S. E. Malenbaum, B. Burke, C. Cheng-Mayer, and L. Stamatatos (2005)
J. Virol. 79, 9069-9080
   Abstract »    Full Text »    PDF »
Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies.
B. F. Haynes, J. Fleming, E. W. St. Clair, H. Katinger, G. Stiegler, R. Kunert, J. Robinson, R. M. Scearce, K. Plonk, H. F. Staats, et al. (2005)
Science 308, 1906-1908
   Abstract »    Full Text »    PDF »
Resistance of Human Immunodeficiency Virus Type 1 to the High-Mannose Binding Agents Cyanovirin N and Concanavalin A.
M. Witvrouw, V. Fikkert, A. Hantson, C. Pannecouque, B. R. O'Keefe, J. McMahon, L. Stamatatos, E. de Clercq, and A. Bolmstedt (2005)
J. Virol. 79, 7777-7784
   Abstract »    Full Text »    PDF »
Analysis of a 17-amino acid residue, virus-neutralizing microantibody.
C. J. Heap, Y. Wang, T. J. T. Pinheiro, S. A. Reading, K. R. Jennings, and N. J. Dimmock (2005)
J. Gen. Virol. 86, 1791-1800
   Abstract »    Full Text »    PDF »
A score matrix to reveal the hidden links in glycans.
K. F. Aoki, H. Mamitsuka, T. Akutsu, and M. Kanehisa (2005)
Bioinformatics 21, 1457-1463
   Abstract »    Full Text »    PDF »
Variants of Human Immunodeficiency Virus Type 1 That Efficiently Use CCR5 Lacking the Tyrosine-Sulfated Amino Terminus Have Adaptive Mutations in gp120, Including Loss of a Functional N-Glycan.
E. J. Platt, D. M. Shea, P. P. Rose, and D. Kabat (2005)
J. Virol. 79, 4357-4368
   Abstract »    Full Text »    PDF »
Anti-Human Immunodeficiency Virus Type 1 (HIV-1) Antibodies 2F5 and 4E10 Require Surprisingly Few Crucial Residues in the Membrane-Proximal External Region of Glycoprotein gp41 To Neutralize HIV-1.
M. B. Zwick, R. Jensen, S. Church, M. Wang, G. Stiegler, R. Kunert, H. Katinger, and D. R. Burton (2005)
J. Virol. 79, 1252-1261
   Abstract »    Full Text »    PDF »
Neutralization Profiles of Newly Transmitted Human Immunodeficiency Virus Type 1 by Monoclonal Antibodies 2G12, 2F5, and 4E10.
S. Mehandru, T. Wrin, J. Galovich, G. Stiegler, B. Vcelar, A. Hurley, C. Hogan, S. Vasan, H. Katinger, C. J. Petropoulos, et al. (2004)
J. Virol. 78, 14039-14042
   Abstract »    Full Text »    PDF »
Printed covalent glycan array for ligand profiling of diverse glycan binding proteins.
O. Blixt, S. Head, T. Mondala, C. Scanlan, M. E. Huflejt, R. Alvarez, M. C. Bryan, F. Fazio, D. Calarese, J. Stevens, et al. (2004)
PNAS 101, 17033-17038
   Abstract »    Full Text »    PDF »
Characterization of the Outer Domain of the gp120 Glycoprotein from Human Immunodeficiency Virus Type 1.
X. Yang, V. Tomov, S. Kurteva, L. Wang, X. Ren, M. K. Gorny, S. Zolla-Pazner, and J. Sodroski (2004)
J. Virol. 78, 12975-12986
   Abstract »    Full Text »    PDF »
Comprehensive Cross-Clade Neutralization Analysis of a Panel of Anti-Human Immunodeficiency Virus Type 1 Monoclonal Antibodies.
J. M. Binley, T. Wrin, B. Korber, M. B. Zwick, M. Wang, C. Chappey, G. Stiegler, R. Kunert, S. Zolla-Pazner, H. Katinger, et al. (2004)
J. Virol. 78, 13232-13252
   Abstract »    Full Text »    PDF »
Evolutionary Dynamics of the Glycan Shield of the Human Immunodeficiency Virus Envelope during Natural Infection and Implications for Exposure of the 2G12 Epitope.
L. Dacheux, A. Moreau, Y. Ataman-Onal, F. Biron, B. Verrier, and F. Barin (2004)
J. Virol. 78, 12625-12637
   Abstract »    Full Text »    PDF »
Structure and Mechanistic Analysis of the Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5 in Complex with Its gp41 Epitope.
G. Ofek, M. Tang, A. Sambor, H. Katinger, J. R. Mascola, R. Wyatt, and P. D. Kwong (2004)
J. Virol. 78, 10724-10737
   Abstract »    Full Text »    PDF »
Improved design of an antigen with enhanced specificity for the broadly HIV-neutralizing antibody b12.
R. Pantophlet, I.A. Wilson, and D.R. Burton (2004)
Protein Eng. Des. Sel. 17, 749-758
   Abstract »    Full Text »    PDF »
Inhibition of Hepatitis C Virus-Like Particle Binding to Target Cells by Antiviral Antibodies in Acute and Chronic Hepatitis C.
D. Steinmann, H. Barth, B. Gissler, P. Schurmann, M. I. Adah, J. T. Gerlach, G. R. Pape, E. Depla, D. Jacobs, G. Maertens, et al. (2004)
J. Virol. 78, 9030-9040
   Abstract »    Full Text »    PDF »
Glycan arrays lead to the discovery of autoimmunogenic activity of SARS-CoV.
D. Wang and J. Lu (2004)
Physiol Genomics 18, 245-248
   Abstract »    Full Text »    PDF »
The V1/V2 Domain of gp120 Is a Global Regulator of the Sensitivity of Primary Human Immunodeficiency Virus Type 1 Isolates to Neutralization by Antibodies Commonly Induced upon Infection.
A. Pinter, W. J. Honnen, Y. He, M. K. Gorny, S. Zolla-Pazner, and S. C. Kayman (2004)
J. Virol. 78, 5205-5215
   Abstract »    Full Text »    PDF »
N-Linked Glycosylation of the V3 Loop and the Immunologically Silent Face of gp120 Protects Human Immunodeficiency Virus Type 1 SF162 from Neutralization by Anti-gp120 and Anti-gp41 Antibodies.
R. A. McCaffrey, C. Saunders, M. Hensel, and L. Stamatatos (2004)
J. Virol. 78, 3279-3295
   Abstract »    Full Text »    PDF »
Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120.
C.-c. Huang, M. Venturi, S. Majeed, M. J. Moore, S. Phogat, M.-Y. Zhang, D. S. Dimitrov, W. A. Hendrickson, J. Robinson, J. Sodroski, et al. (2004)
PNAS 101, 2706-2711
   Abstract »    Full Text »    PDF »
Structure and Molecular Interactions of a Unique Antitumor Antibody Specific for N-Glycolyl GM3.
U. Krengel, L.-L. Olsson, C. Martinez, A. Talavera, G. Rojas, E. Mier, J. Angstrom, and E. Moreno (2004)
J. Biol. Chem. 279, 5597-5603
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)