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

Journal Article · · Immunity
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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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health; National Cancer Inst.; National Inst. of General Medical Sciences
Grant/Contract Number:
AC02-06CH11357; R01 AI118985; R01 GM117424; R21 AI121918; R21 AI122211; R01 GM071872; ACB-12002; AGM-12006
OSTI ID:
1458844
Alternate ID(s):
OSTI ID: 1372230
Journal Information:
Immunity, Journal Name: Immunity Vol. 46 Journal Issue: 6; ISSN 1074-7613
Publisher:
Cell PressCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 121 works
Citation information provided by
Web of Science

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Chemokine antagonist
HIV entry inhibitor
CCL5/RANTES
CCR5-gp120 interaction
G protein-coupled receptor (GPCR)
viral mimicry
membrane protein structure
maraviroc
two-site model
V3 loop