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-Structure paper
タイトル | Structure of GPR101-Gs enables identification of ligands with rejuvenating potential. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 20, Issue 4, Page 484-492, Year 2024 |
掲載日 | 2023年11月9日 |
著者 | Zhao Yang / Jun-Yan Wang / Fan Yang / Kong-Kai Zhu / Guo-Peng Wang / Ying Guan / Shang-Lei 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 / Bao-Hua Liu / Hua Zhang / Xiao Yu / Ning Gao / Jin-Peng Sun / |
PubMed 要旨 | 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, ...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. |
リンク | Nat Chem Biol / PubMed:37945893 |
手法 | EM (単粒子) |
解像度 | 2.89 - 3.3 Å |
構造データ | EMDB-37356, PDB-8w8q: EMDB-37357, PDB-8w8r: EMDB-37358, PDB-8w8s: |
化合物 | ChemComp-U7D: |
由来 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / GPCR (Gタンパク質共役受容体) / orphan receptor (オーファン受容体) / GPR101 / constitutive activity (受容体) / cryo-EM (低温電子顕微鏡法) / structural protein (タンパク質) |