Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China.
Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Mol Cell. 2023 Sep 7;83(17):3171-3187.e7. doi: 10.1016/j.molcel.2023.07.030. Epub 2023 Aug 18.
Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G protein or β-arrestin effectors. Here, we characterize compound 9n as a G-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G pathway. Furthermore, four structures of HCAR2-G complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.
羟基羧酸受体 2 (HCAR2) 受内源性酮体 β-羟丁酸和外源性烟酸调节，是一种有前途的炎症相关疾病治疗靶点。HCAR2 通过激活 G 蛋白或β-arrestin 效应器来介导不同的病理生理事件。在这里，我们将化合物 9n 鉴定为 HCAR2 的 G 偏向变构调节剂 (BAM)，并通过特定的 HCAR2-G 途径在 RAW264.7 巨噬细胞中表现出抗炎功效。此外，结合共晶结构，我们揭示了 HCAR2-G 复合物与变构激动剂（烟酸或单甲基富马酸）、化合物 9n 以及烟酸与化合物 9n 同时结合的共四个结构，揭示了一个共同的正位结合位点和一个独特的变构结合位点。结合功能研究，我们阐明了化合物 9n 对正位结合位点的变构调节作用的作用机制。此外，化合物 9n 与正位激动剂联合给药可增强结肠炎小鼠模型中的抗炎作用。总之，我们的研究提供了对 BAM 变构调节的分子药理学的深入了解，并促进了与正位药物联合探索 BAM 的治疗潜力。
