Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Signal Transduct Target Ther. 2023 Sep 25;8(1):364. doi: 10.1038/s41392-023-01625-y.
Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of G-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 Å. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands.
羟基羧酸受体 2（HCAR2）是 A 类 G 蛋白偶联受体（GPCR）家族的成员，在抗脂肪分解和抗炎作用中发挥着关键作用，使其成为治疗血脂异常和炎症性疾病的重要治疗靶点。然而，各种配体诱导的 HCAR2 信号转导的机制仍不清楚。在这项研究中，我们阐明了与选择性激动剂 MK-6892 结合的 G 偶联 HCAR2 的冷冻电子显微镜（cryo-EM）结构，分辨率为 2.60Å。我们的结构分析表明，MK-6892 不仅占据了 HCAR2 的正位结合口袋（OBP），还占据了一个扩展的结合口袋（EBP）。本研究中的药理学研究表明，OBP 是 HCAR 亚家族中配体选择性的关键决定因素。此外，我们研究了变构调节剂化合物 9n 的药理学特性，揭示了其在不同正位激动剂存在下对 HCAR2 的探针依赖性行为。总之，我们的研究结果提供了宝贵的结构见解，有助于深入了解正位和变构配体介导的 HCAR2 信号转导的调节机制。
