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Science 10 August 2001:
Vol. 293. no. 5532, pp. 1155 - 1159
DOI: 10.1126/science.1061692
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Reports

Crystal Structure of a Neutralizing Human IgG Against HIV-1: A Template for Vaccine Design

Erica Ollmann Saphire,1 Paul W. H. I. Parren,2 Ralph Pantophlet,2 Michael B. Zwick,2 Garrett M. Morris,1 Pauline M. Rudd,4 Raymond A. Dwek,4 Robyn L. Stanfield,1 Dennis R. Burton,12* Ian A. Wilson13*

We present the crystal structure at 2.7 angstrom resolution of the human antibody IgG1 b12. Antibody b12 recognizes the CD4-binding site of human immunodeficiency virus-1 (HIV-1) gp120 and is one of only two known antibodies against gp120 capable of broad and potent neutralization of primary HIV-1 isolates. A key feature of the antibody-combining site is the protruding, finger-like long CDR H3 that can penetrate the recessed CD4-binding site of gp120. A docking model of b12 and gp120 reveals severe structural constraints that explain the extraordinary challenge in eliciting effective neutralizing antibodies similar to b12. The structure, together with mutagenesis studies, provides a rationale for the extensive cross-reactivity of b12 and a valuable framework for the design of HIV-1 vaccines capable of eliciting b12-like activity.

1 Department of Molecular Biology,
2 Department of Immunology,
3 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Department of Biochemistry, University of Oxford, The Oxford Glycobiology Institute, South Parks Road, Oxford OX1 3QU, UK.
*   To whom correspondence should be addressed. E-mail: wilson{at}scripps.edu, burton{at}scripps.edu

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Molecular Features of the Broadly Neutralizing Immunoglobulin G1 b12 Required for Recognition of Human Immunodeficiency Virus Type 1 gp120.
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J. Virol. 77, 5863-5876
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Fine Mapping of the Interaction of Neutralizing and Nonneutralizing Monoclonal Antibodies with the CD4 Binding Site of Human Immunodeficiency Virus Type 1 gp120.
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J. Virol. 77, 642-658
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B. Gaschen, J. Taylor, K. Yusim, B. Foley, F. Gao, D. Lang, V. Novitsky, B. Haynes, B. H. Hahn, T. Bhattacharya, et al. (2002)
Science 296, 2354-2360
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Broadly Neutralizing Antibodies Targeted to the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 Glycoprotein gp41.
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