5t1a | pdb_00005t1a

Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists

spinqualitylabelsall models 5t1a, resolution 2.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5t1a is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 73R, OLC, SO4, VT5, ZN NonStd Res: YCM Gene: e, T4Tp126 (HUMAN) Activity: Lysozyme, with EC number 3.2.1.17 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CCR2_HUMAN] Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection. Publication Abstract from PubMed 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 https://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. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.,Zheng Y, Qin L, Zacarias NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM Nature. 2016 Dec 7. doi: 10.1038/nature20605. PMID:27926736 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Lysozyme 3D structures

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