Yang Zhao, Wang Jun-Yan, Yang Fan, Zhu Kong-Kai, Wang Guo-Peng, Guan Ying, Ning Shang-Lei, Lu Yan, Li Yu, Zhang Chao, Zheng Yuan, Zhou Shu-Hua, Wang Xin-Wen, Wang Ming-Wei, Xiao Peng, Yi Fan, Zhang Cheng, Zhang Peng-Ju, Xu Fei, Liu Bao-Hua, Zhang Hua, Yu Xiao, Gao Ning, Sun Jin-Peng
NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
Nat Chem Biol. 2024 Apr;20(4):484-492. doi: 10.1038/s41589-023-01456-6. Epub 2023 Nov 9.
GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.
GPR101是一种积极参与能量稳态的孤儿G蛋白偶联受体。在此，我们报告了与Gs异源三聚体组成性偶联的GPR101的冷冻电镜结构，该结构揭示了GPR101的独特特征，包括7次跨膜结构域束内细胞外环2的相互作用、疏水链堆积介导的激活机制以及疾病相关突变体的结构基础。重要的是，在GPR101中鉴定出一个侧袋，便于通过计算机筛选鉴定出四种小分子激动剂，包括AA - 14。AA - 14 - GPR101 - Gs的结构为AA - 14在侧袋处的结合提供了直接证据。在功能上，AA - 14部分恢复了生长激素/胰岛素样生长因子-1轴的功能，并在野生型小鼠中表现出多种回春效应，而在Gpr101基因敲除小鼠中这些效应被消除。总之，我们为GPR101的组成性活性提供了结构基础。基于结构鉴定出的GPR101激动剂以及功能分析表明，靶向这个孤儿受体具有回春潜力。
