Article

Nature 393, 648-659 (18 June 1998) | doi:10.1038/31405; Received 15 May 1998; Accepted 28 May 1998

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Peter D. Kwong1, Richard Wyatt2, James Robinson3, Raymond W. Sweet4, Joseph Sodroski2,5 & Wayne A. Hendrickson1,6

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
  2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  3. Department of Pediatrics, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA
  4. Department of Immunology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA
  5. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  6. Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA

Correspondence to: Wayne A. Hendrickson1,6 Correspondence and requests for materials should be addressed to W.A.H. (e-mail: Email: wayne@convex.hhmi.columbia.edu). Coordinates have been deposited in the Brookhaven Protein Data Bank (accession code 1gc1) and may be obtained from the authors.

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The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gpl20 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 Å resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4–gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene.