Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
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DOI：
10.1038/s41589-023-01456-6
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发表时间：
2023-11
影响因子：
14.8
通讯作者：
Zhao Yang;Junyan Wang;Fan Yang;Kong-kai Zhu;Guo-Peng Wang;Ying Guan;S. Ning;Yan Lu;Yu Li;Chao Zhang;Yuan Zheng;Shu-Hua Zhou;Xin-Wen Wang;Ming-Wei Wang;Peng Xiao;Fan Yi;Cheng Zhang;Peng-Ju Zhang;Fei Xu;Baohua Liu;Hua Zhang;Xiao Yu;N. Gao;Jin-Peng Sun
中科院分区：
文献类型：
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作者：
Zhao Yang;Junyan Wang;Fan Yang;Kong-kai Zhu;Guo-Peng Wang;Ying Guan;S. Ning;Yan Lu;Yu Li;Chao Zhang;Yuan Zheng;Shu-Hua Zhou;Xin-Wen Wang;Ming-Wei Wang;Peng Xiao;Fan Yi;Cheng Zhang;Peng-Ju Zhang;Fei Xu;Baohua Liu;Hua Zhang;Xiao Yu;N. Gao;Jin-Peng Sun
GPR101是一种孤儿G蛋白偶联受体，积极参与能量稳态。在这里，我们报道了GPR101与Gs异源三聚体组成偶联的冷冻电子显微镜结构，揭示了GPR101的独特特征，包括7TM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中发现了一个侧袋，它有助于进行电子筛选，以识别包括AA-14在内的四种小分子激动剂。AA-14-GPR101-Gs的结构提供了AA-14在侧袋结合的直接证据。在功能上，AA-14部分恢复了GH/IGF-1轴的功能，并在Gpr101缺陷小鼠中被取消的野生型小鼠表现出几种返老还童的作用。综上所述，我们为GPR101的结构性活性提供了结构基础。GPR101激动剂的结构易化鉴定和功能分析表明，靶向这种孤儿受体具有恢复活力的潜力。
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 inGpr101-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.