Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer

Nat Struct Mol Biol. 2017 Apr;24(4):370-378. doi: 10.1038/nsmb.3382. Epub 2017 Feb 20.


Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1-Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / metabolism
  • Binding Sites
  • CD4 Antigens / chemistry*
  • CD4 Antigens / metabolism*
  • CD4 Antigens / ultrastructure
  • Cryoelectron Microscopy
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Envelope Protein gp120 / ultrastructure
  • HIV Infections / metabolism
  • HIV-1 / metabolism*
  • Humans
  • Kinetics
  • Mutagenesis
  • Protein Binding
  • Protein Multimerization*
  • Protein Stability
  • Protein Structure, Quaternary
  • Surface Plasmon Resonance


  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp120