skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

Abstract

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles themore » most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1342236
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature (London); Journal Volume: 540; Journal Issue: 7633
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Zheng, Yi, Qin, Ling, Zacarías, Natalia V. Ortiz, de Vries, Henk, Han, Gye Won, Gustavsson, Martin, Dabros, Marta, Zhao, Chunxia, Cherney, Robert J., Carter, Percy, Stamos, Dean, Abagyan, Ruben, Cherezov, Vadim, Stevens, Raymond C., IJzerman, Adriaan P., Heitman, Laura H., Tebben, Andrew, Kufareva, Irina, and Handel, Tracy M. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. United States: N. p., 2016. Web. doi:10.1038/nature20605.
Zheng, Yi, Qin, Ling, Zacarías, Natalia V. Ortiz, de Vries, Henk, Han, Gye Won, Gustavsson, Martin, Dabros, Marta, Zhao, Chunxia, Cherney, Robert J., Carter, Percy, Stamos, Dean, Abagyan, Ruben, Cherezov, Vadim, Stevens, Raymond C., IJzerman, Adriaan P., Heitman, Laura H., Tebben, Andrew, Kufareva, Irina, & Handel, Tracy M. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. United States. doi:10.1038/nature20605.
Zheng, Yi, Qin, Ling, Zacarías, Natalia V. Ortiz, de Vries, Henk, Han, Gye Won, Gustavsson, Martin, Dabros, Marta, Zhao, Chunxia, Cherney, Robert J., Carter, Percy, Stamos, Dean, Abagyan, Ruben, Cherezov, Vadim, Stevens, Raymond C., IJzerman, Adriaan P., Heitman, Laura H., Tebben, Andrew, Kufareva, Irina, and Handel, Tracy M. Wed . "Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists". United States. doi:10.1038/nature20605.
@article{osti_1342236,
title = {Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists},
author = {Zheng, Yi and Qin, Ling and Zacarías, Natalia V. Ortiz and de Vries, Henk and Han, Gye Won and Gustavsson, Martin and Dabros, Marta and Zhao, Chunxia and Cherney, Robert J. and Carter, Percy and Stamos, Dean and Abagyan, Ruben and Cherezov, Vadim and Stevens, Raymond C. and IJzerman, Adriaan P. and Heitman, Laura H. and Tebben, Andrew and Kufareva, Irina and Handel, Tracy M.},
abstractNote = {CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.},
doi = {10.1038/nature20605},
journal = {Nature (London)},
number = 7633,
volume = 540,
place = {United States},
year = {Wed Dec 07 00:00:00 EST 2016},
month = {Wed Dec 07 00:00:00 EST 2016}
}