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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

Abstract

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.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health; National Cancer Inst.; National Inst. of General Medical Sciences
OSTI Identifier:
1458844
Alternate Identifier(s):
OSTI ID: 1372230
Grant/Contract Number:  
AC02-06CH11357; R01 AI118985; R01 GM117424; R21 AI121918; R21 AI122211; R01 GM071872; ACB-12002; AGM-12006
Resource Type:
Published Article
Journal Name:
Immunity
Additional Journal Information:
Journal Name: Immunity Journal Volume: 46 Journal Issue: 6; Journal ID: ISSN 1074-7613
Publisher:
Cell Press
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

Zheng, Yi, Han, Gye Won, Abagyan, Ruben, Wu, Beili, Stevens, Raymond C., Cherezov, Vadim, Kufareva, Irina, and Handel, Tracy M. Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. United States: N. p., 2017. Web. doi:10.1016/j.immuni.2017.05.002.
Zheng, Yi, Han, Gye Won, Abagyan, Ruben, Wu, Beili, Stevens, Raymond C., Cherezov, Vadim, Kufareva, Irina, & Handel, Tracy M. Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. United States. doi:10.1016/j.immuni.2017.05.002.
Zheng, Yi, Han, Gye Won, Abagyan, Ruben, Wu, Beili, Stevens, Raymond C., Cherezov, Vadim, Kufareva, Irina, and Handel, Tracy M. Thu . "Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV". United States. doi:10.1016/j.immuni.2017.05.002.
@article{osti_1458844,
title = {Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV},
author = {Zheng, Yi and Han, Gye Won and Abagyan, Ruben and Wu, Beili and Stevens, Raymond C. and Cherezov, Vadim and Kufareva, Irina and Handel, Tracy M.},
abstractNote = {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.},
doi = {10.1016/j.immuni.2017.05.002},
journal = {Immunity},
number = 6,
volume = 46,
place = {United States},
year = {2017},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.immuni.2017.05.002

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Cited by: 51 works
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