Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.
Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.
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DOI：
10.1038/nature20605
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发表时间：
2016-12-15
期刊：
影响因子：
64.8
通讯作者：
Handel, Tracy M.
中科院分区：
文献类型：
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作者：
Zheng, Yi;Qin, Ling;Zacarias, Natalia V. Ortiz;de Vries, Henk;Han, Gye Won;Gustavsson, Martin;Dabros, Marta;Zhao, Chunxia;Cherney, Robert J.;Carter, Percy;Stamos, Dean;Abagyan, Ruben;Cherezov, Vadim;Stevens, Raymond C.;Ijzerman, Adriaan P.;Heitman, Laura H.;Tebben, Andrew;Kufareva, Irina;Handel, Tracy M.
CC趋化因子受体2 （CCR2）是人A类G蛋白偶联受体（gpcr）趋化因子受体亚家族的19个成员之一。CCR2在单核细胞、未成熟树突状细胞和T细胞亚群中表达，并介导它们向内源性CC趋化因子配体（如CCL2）迁移。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、多发性硬化症、哮喘、神经性疼痛、糖尿病肾病以及癌症。这些疾病的关联促使了许多临床前研究和临床试验（见ClinicalTrials.gov）寻找针对CCR2趋化因子轴的治疗方法。为了帮助药物发现，我们研究了CCR2与正构（BMS-681）和变构（CCR2- ra -[R]）拮抗剂的三元配合物的结构。BMS-681通过以一种以前未见过的结合模式占据受体的正位口袋来抑制趋化因子的结合。CCR2-RA-[R]结合在一个新的、高度可药物化的口袋中，这是迄今为止在a类gpcr中观察到的最多的细胞内变抗位点；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不活跃的GPCR结构。与其他蛋白质：蛋白质相互作用一样，受体：趋化因子复合物被认为是小分子具有挑战性的治疗靶点，目前的结构表明可以利用不同的口袋表位来克服药物设计障碍。
CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human Class A G protein-coupled receptors (GPCRs). CCR2 is expressed on monocytes, immature dendritic cells and T cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2. 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 ClinicalTrials.gov) in search of therapies that target the CCR2:chemokine axis. To aid drug discovery efforts, we solved a structure of CCR2 in a ternary complex with an orthosteric (BMS-681) 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 GPCRs to date; 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 GPCR structures solved to date. 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 drug design obstacles.
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影响因子：
64.5
作者：
Manglik A;Kim TH;Masureel M;Altenbach C;Yang Z;Hilger D;Lerch MT;Kobilka TS;Thian FS;Hubbell WL;Prosser RS;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
64.8
作者：
Hino, Tomoya;Arakawa, Takatoshi;Iwanari, Hiroko;Yurugi-Kobayashi, Takami;Ikeda-Suno, Chiyo;Nakada-Nakura, Yoshiko;Kusano-Arai, Osamu;Weyand, Simone;Shimamura, Tatsuro;Nomura, Norimichi;Cameron, Alexander D.;Kobayashi, Takuya;Hamakubo, Takao;Iwata, So;Murata, Takeshi
通讯作者：
Murata, Takeshi
影响因子：
4.4
作者：
Brodmerkel, CM;Huber, R;Vaddi, K
通讯作者：
Vaddi, K
DOI：
10.2174/1871530315666150316120920
发表时间：
2015-01-01
影响因子：
1.9
作者：
O'Connor, Tracy;Borsig, Lubor;Heikenwalder, Mathias
通讯作者：
Heikenwalder, Mathias
影响因子：
14.8
作者：
通讯作者：
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