The human CC chemokine receptor 5 (CCR5) is a G protein–coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric G_i protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.

人类 CC 趋化因子受体 5 (CCR5) 是一种 G 蛋白偶联受体 (GPCR)，在炎症中起主要作用，并参与癌症、HIV 和 COVID-19。尽管它作为药物靶点很重要，但 CCR5 的分子激活机制，即趋化因子激动剂如何通过受体转导激活信号，尚不清楚。在这里，我们报告了与趋化因子超级激动剂 [6P4]CCL5 和异源三聚体 G _i结合的活性构象中野生型 CCR5 的冷冻电镜结构蛋白质。该结构为激动剂和拮抗剂趋化因子的序列-活性关系提供了基本原理。激动剂趋化因子的 N 末端推动正构口袋底部的特定结构基序，激活规范 GPCR 微开关网络。这种激活机制与其他 CC 趋化因子受体显着不同，其他 CC 趋化因子受体以浅层结合模式结合具有较短 N 末端的趋化因子，涉及独特的序列特征和专门的激活机制。