Structural definition of a conserved neutralization epitope on HIV-1 gp120

Nature. 2007 Feb 15;445(7129):732-7. doi: 10.1038/nature05580.

Abstract

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism
  • Conserved Sequence*
  • Epitopes / chemistry*
  • Epitopes / immunology
  • HIV Antibodies / immunology*
  • HIV Antibodies / pharmacology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / chemistry*
  • HIV-1 / drug effects
  • HIV-1 / immunology*
  • HIV-1 / physiology
  • Models, Molecular
  • Molecular Weight
  • Neutralization Tests
  • Protein Conformation

Substances

  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120

Associated data

  • PDB/2NXY
  • PDB/2NY6
  • PDB/2NY7