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 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 http://www.clinicaltrials.gov) 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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
authors.forename: Natalia V Ortiz
authors.initials: NV
authors.lastname: Zacarías
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.affiliation: Bridge Institute, Departments of Chemistry and Physics &Astronomy, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Gustavsson
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Dabros
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA.
authors.forename: Percy
authors.initials: P
authors.lastname: Carter
authors.affiliation: Vertex Pharmaceuticals Inc., 11010 Torreyana Road, San Diego, California 92121, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Bridge Institute, Departments of Chemistry and Physics &Astronomy, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.affiliation: The Bridge Institute, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden 2333 CC, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tebben
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D001665:Binding Sites; D019742:Chemokines, CC / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: C000616912:BMS-681; C000616913:CCR2-RA compound; D019742:Chemokines, CC; D008024:Ligands; D011760:Pyrrolidinones; D011799:Quinazolines; D054390:Receptors, CCR2; D020962:Heterotrimeric GTP-Binding Proteins