8w8s

Cryo-EM structure of the AA14-bound GPR101 complex

spinqualitylabelsall models 8w8s, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8w8s is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: U7D Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.,Yang Z, Wang JY, Yang F, Zhu KK, Wang GP, Guan Y, Ning SL, Lu Y, Li Y, Zhang C, Zheng Y, Zhou SH, Wang XW, Wang MW, Xiao P, Yi F, Zhang C, Zhang PJ, Xu F, Liu BH, Zhang H, Yu X, Gao N, Sun JP Nat Chem Biol. 2024 Apr;20(4):484-492. doi: 10.1038/s41589-023-01456-6. Epub 2023 , Nov 9. PMID:37945893 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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