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Nature. 2016 Dec 15;540(7633):458-461. doi: 10.1038/nature20605. Epub 2016 Dec 7.

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.

Author information

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
Bridge Institute, Departments of Chemistry and Physics &Astronomy, University of Southern California, Los Angeles, California 90089, USA.
Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA.
Vertex Pharmaceuticals Inc., 11010 Torreyana Road, San Diego, California 92121, USA.
The Bridge Institute, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California 90089, USA.


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 diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) 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.

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Conflict of interest statement

Competing interest declaration R.A. has an equity interest in Molsoft, LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. R.C., P.C., and A.T. are employees of Bristol-Myers Squibb Company. D.S. is an employee of Vertex Pharmaceuticals, Inc.

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