Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV

Immunity. 2017 Jun 20;46(6):1005-1017.e5. doi: 10.1016/j.immuni.2017.05.002.


CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

Keywords: CCL5/RANTES; CCR5-gp120 interaction; Chemokine antagonist; G protein-coupled receptor (GPCR); HIV entry inhibitor; V3 loop; maraviroc; membrane protein structure; two-site model; viral mimicry.

MeSH terms

  • Animals
  • CCR5 Receptor Antagonists / chemistry
  • CCR5 Receptor Antagonists / pharmacology
  • Chemokine CCL5 / chemistry*
  • Chemokine CCL5 / metabolism
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / metabolism
  • HIV Fusion Inhibitors / chemistry
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV-1 / physiology*
  • Humans
  • Maraviroc
  • Models, Molecular*
  • Molecular Mimicry*
  • Protein Binding
  • Protein Conformation
  • Receptors, CCR5 / chemistry*
  • Receptors, CCR5 / metabolism
  • Sf9 Cells
  • Spodoptera
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology
  • Virus Internalization / drug effects


  • CCR5 Receptor Antagonists
  • Chemokine CCL5
  • Cyclohexanes
  • HIV Envelope Protein gp120
  • HIV Fusion Inhibitors
  • Receptors, CCR5
  • Triazoles
  • Maraviroc