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Cryo-EM structure of the P395-bound GPBAR-Gs complexCryo-EM structure of the P395-bound GPBAR-Gs complex
Structural highlights
Publication Abstract from PubMedThe G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver-bile-acid-microbiota-metabolism axis(1-3). Here, we report the cryo-EM structures of GPBAR-Gs complexes stabilized by either the high-affinity P395(4) or the semisynthesized bile acid derivative INT-777(1,3) at 3-A resolution. These structures revealed a large oval-shaped pocket containing several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily. Structural basis of GPBAR activation and bile acid recognition.,Yang F, Mao C, Guo L, Lin J, Ming Q, Xiao P, Wu X, Shen Q, Guo S, Shen DD, Lu R, Zhang L, Huang S, Ping Y, Zhang C, Ma C, Zhang K, Liang X, Shen Y, Nan F, Yi F, Luca VC, Zhou J, Jiang C, Sun JP, Xie X, Yu X, Zhang Y Nature. 2020 Jul 22. pii: 10.1038/s41586-020-2569-1. doi:, 10.1038/s41586-020-2569-1. PMID:32698187[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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