Structural basis of coreceptor recognition by HIV-1 envelope spike

Nature. 2019 Jan;565(7739):318-323. doi: 10.1038/s41586-018-0804-9. Epub 2018 Dec 12.


HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160)3 cleaved to (gp120 and gp41)3, interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120-coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and the N terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry into host cells and may guide the development of vaccines and therapeutic agents.

Publication types

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

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Binding Sites
  • CD4 Antigens / chemistry*
  • CD4 Antigens / isolation & purification
  • CD4 Antigens / metabolism
  • CD4 Antigens / ultrastructure*
  • Cell Line
  • Chemokine CCL5 / chemistry
  • Chemokine CCL5 / metabolism
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / isolation & purification
  • HIV Envelope Protein gp120 / metabolism
  • HIV Envelope Protein gp120 / ultrastructure*
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / metabolism
  • HIV Envelope Protein gp41 / ultrastructure
  • Humans
  • Ligands
  • Maraviroc / chemistry
  • Maraviroc / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Receptors, CCR5 / chemistry*
  • Receptors, CCR5 / isolation & purification
  • Receptors, CCR5 / metabolism
  • Receptors, CCR5 / ultrastructure*
  • Receptors, HIV / antagonists & inhibitors
  • Receptors, HIV / chemistry*
  • Receptors, HIV / metabolism
  • Receptors, HIV / ultrastructure*


  • Anti-HIV Agents
  • CCR5 protein, human
  • CD4 Antigens
  • Chemokine CCL5
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • Ligands
  • Receptors, CCR5
  • Receptors, HIV
  • Maraviroc