5T1A

Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists

Summary for 5T1A

• Entry DOI: 10.2210/pdb5t1a/pdb
• Descriptor: Chimera protein of CC chemokine receptor type 2 isoform B and T4-lysozyme,Lysozyme, (3S)-1-{(1S,2R,4R)-4-[methyl(propan-2-yl)amino]-2-propylcyclohexyl}-3-{[6-(trifluoromethyl)quinazolin-4-yl]amino}pyrrolidin-2-one, (2~{R})-1-(4-chloranyl-2-fluoranyl-phenyl)-2-cyclohexyl-3-ethanoyl-4-oxidanyl-2~{H}-pyrrol-5-one, ... (7 entities in total)
• Functional Keywords: c-c chemokine receptor type 2, dual antagonist, intracellular allosteric antagonist, cooperative binding, lipidic cubic phase, membrane protein, gpcr, structural genomics, psi-2, protein structure initiative, gpcr network, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 59577.95

Authors

Zheng, Y.,Qin, L.,Ortiz Zacarias, N.V.,de Vries, H.,Han, G.W.,Gustavsson, M.,Dabros, M.,Zhao, C.,Cherney, R.J.,Carter, P.,Stamos, D.,Abagyan, R.,Cherezov, V.,Stevens, R.C.,IJzerman, A.P.,Heitman, L.H.,Tebben, A.,Kufareva, I.,Handel, T.M. (deposition date: 2016-08-18, release date: 2016-12-14, Last modification date: 2023-10-04)

Primary citation

Zheng, Y.,Qin, L.,Zacarias, N.V.,de Vries, H.,Han, G.W.,Gustavsson, M.,Dabros, M.,Zhao, C.,Cherney, R.J.,Carter, P.,Stamos, D.,Abagyan, R.,Cherezov, V.,Stevens, R.C.,IJzerman, A.P.,Heitman, L.H.,Tebben, A.,Kufareva, I.,Handel, T.M.
Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.
Nature, 540:458-461, 2016

PubMed 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.

PubMed: 27926736
DOI: 10.1038/nature20605

Experimental method

X-RAY DIFFRACTION (2.806 Å)