Intracellular allosteric antagonism of the CCR9 receptor
Intracellular allosteric antagonism of the CCR9 receptor
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DOI：
10.1038/nature20606
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发表时间：
2016-12-15
期刊：
影响因子：
64.8
通讯作者：
Marshall, Fiona H.
中科院分区：
文献类型：
--
作者：
Oswald, Christine;Rappas, Mathieu;Marshall, Fiona H.
趋化因子及其G蛋白偶联受体通过控制免疫细胞的迁移、激活和存活，在免疫防御中发挥不同的作用(1)。它们还参与病毒进入、肿瘤生长和转移，因此是治疗多种疾病的重要药物靶点(2，3)。尽管制药业在开发药物方面做出了巨大努力，有50多种小分子药物进入临床开发，但只有两种化合物进入市场：用于艾滋病毒感染的马拉韦罗(CCR5)和用于干细胞动员的普利沙福(CXCR4)。失败率高的部分原因可能是对趋化因子拮抗剂作用机制的了解有限，以及在缺乏结构信息的情况下无法优化化合物(5)。CCL25激活CC趋化因子受体9(CCR9)在白细胞募集到肠道中起关键作用，是炎症性肠病的治疗靶点(6)。选择性CCR9拮抗剂马鞭草进入克罗恩病的3期临床试验，但疗效有限，需要非常高的剂量来阻断受体的激活(6)。在此，我们报道了CCR9受体在2.8埃分辨率下与马鞭草酮的络合物的晶体结构。值得注意的是，马鞭草能与受体的胞内侧结合，发挥变构拮抗作用，防止G蛋白偶联。这个结合位点解释了为什么需要相对亲脂的配体，并描述了G蛋白偶联受体(7)上的变构位点的另一个例子，它不仅可以用于药物设计，而且可能延伸到其他趋化因子受体。
Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells(1). They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases(2,3). Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization4. The high failure rate may in part be due to limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information(5). CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease(6). The selective CCR9 antagonist vercirnon progressed to phase 3 clinical trials in Crohn's disease but efficacy was limited, with the need for very high doses to block receptor activation(6). Here we report the crystal structure of the CCR9 receptor in complex with vercirnon at 2.8 angstrom resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors(7) that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.