Ke Yudun, Huang Yimiao, Yi Cuiying, Ma Limin, Chu Xiaojing, Wu Beili, Zhao Qiang, Han Shuo
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cell Rep. 2024 Dec 24;43(12):115024. doi: 10.1016/j.celrep.2024.115024. Epub 2024 Nov 30.
Free fatty acid receptors (FFARs) play critical roles in metabolic regulation and are potential therapeutic targets for metabolic and inflammatory diseases. A comprehensive understanding of the activation mechanisms and endogenous ligand selectivity of FFARs is essential for drug discovery. Here, we report two cryoelectron microscopy structures of the human FFAR1 bound to the endogenous ligand docosahexaenoic acid (DHA) and G protein as well as FFAR2 in complex with butyrate and G at 3.2 Å and 3.3 Å resolution, respectively. These structures highlight that distinct locations and sizes of the orthosteric ligand binding pockets are crucial determinants of the endogenous ligand selectivity of this receptor subfamily. Additionally, computational analysis reveals a potential allosteric ligand binding pocket in FFAR2. Furthermore, we observe that the upward movement of helix V upon endogenous ligand binding is responsible for receptor activation. These insights will significantly aid in the development of drugs targeting this receptor family.
游离脂肪酸受体（FFARs）在代谢调节中发挥关键作用，是代谢和炎症性疾病的潜在治疗靶点。全面了解FFARs的激活机制和内源性配体选择性对于药物发现至关重要。在此，我们报告了人FFAR1与内源性配体二十二碳六烯酸（DHA）和G蛋白结合以及FFAR2与丁酸和G蛋白复合物的两个冷冻电镜结构，分辨率分别为3.2 Å和3.3 Å。这些结构突出表明，正构配体结合口袋的不同位置和大小是该受体亚家族内源性配体选择性的关键决定因素。此外，计算分析揭示了FFAR2中一个潜在的变构配体结合口袋。此外，我们观察到内源性配体结合后螺旋V的向上移动负责受体激活。这些见解将极大地有助于开发针对该受体家族的药物。
