CC趋化因子受体2的结构与正构和变构拮抗剂,Nature

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CC趋化因子受体2的结构与正构和变构拮抗剂
Nature ( IF 50.5 ) Pub Date : 2016-12-07 , DOI: 10.1038/nature20605
Yi Zheng , Ling Qin , Natalia V. Ortiz Zacarías , Henk de Vries , Gye Won Han , Martin Gustavsson , Marta Dabros , Chunxia Zhao , Robert J. Cherney , Percy Carter , Dean Stamos , Ruben Abagyan , Vadim Cherezov , Raymond C. Stevens , Adriaan P. IJzerman , Laura H. Heitman , Andrew Tebben , Irina Kufareva , Tracy M. Handel

CC 趋化因子受体 2 (CCR2) 是人类 A 类 G 蛋白偶联受体趋化因子受体亚家族的 19 个成员之一。CCR2 在单核细胞、未成熟树突细胞和 T 细胞亚群上表达，并介导它们向内源性 CC 趋化因子配体（如 CCL2）迁移（参考文献 1）。CCR2 及其配体与许多炎症和神经退行性疾病有关，包括动脉粥样硬化、多发性硬化、哮喘、神经性疼痛和糖尿病肾病以及癌症。这些疾病关联激发了大量临床前研究和临床试验（参见 http://www.clinicaltrials.gov）以寻找针对 CCR2-趋化因子轴的疗法。为了帮助药物发现工作，我们在这里解决了具有正构（BMS-681（参考文献）的三元复合物中的 CCR2 结构）。6)) 和变构 (CCR2-RA-[R]) 拮抗剂。BMS-681 通过以先前未见的结合模式占据受体的正构口袋来抑制趋化因子结合。CCR2-RA-[R] 结合在一个新的、高度可成药的口袋中，这是迄今为止在 A 类 G 蛋白偶联受体中观察到的最多的细胞内变构位点；该位点在空间上与同源受体中的 G 蛋白结合位点重叠。CCR2-RA-[R] 通过阻断激活相关的构象变化和 G 蛋白结合界面的形成，非竞争性地抑制 CCR2。在双拮抗剂结合的 CCR2 中观察到的保守微开关残基的构象特征类似于迄今为止解决的最无活性的 G 蛋白偶联受体结构。像其他蛋白质-蛋白质相互作用一样，

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Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

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.

更新日期：2016-12-07

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