Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Clinical Laboratory, The Second Hospital, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
Nat Chem Biol. 2022 Nov;18(11):1196-1203. doi: 10.1038/s41589-022-01084-6. Epub 2022 Aug 18.
Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a G trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-G provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.
黏附 G 蛋白偶联受体在结构信息和配体方面难以捉摸。在这里，我们解决了冷冻电镜（cryo-EM）结构的 apo-ADGRG2，一个对于维持男性生育能力至关重要的膜受体，与 G 三聚体复合。虽然两个扭曲的形成是活性状态的决定因素，但在 ADGRG2 中鉴定出一个潜在的配体结合口袋，促进了脱氢表雄酮（DHEA）、硫酸脱氢表雄酮和脱氧皮质酮作为 ADGRG2 的潜在配体的筛选和鉴定。DHEA-ADGRG2-G 的 cryo-EM 结构提供了 DHEA 在 ADGRG2 的七个跨膜结构域内的相互作用细节。总的来说，我们的数据为 ADGRG2 的激活和信号转导提供了结构基础，以及类固醇激素作为 ADGRG2 配体的特征，这可能被用作进一步研究孤儿 ADGRG2 的功能的有用工具。
