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Title: Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias
Authors: Maeda, Shintaro
Shiimura, Yuki
Asada, Hidetsugu
Hirata, Kunio
Luo, Fangjia
Nango, Eriko
Tanaka, Nobuo
Toyomoto, Masayasu
Inoue, Asuka
Aoki, Junken
Iwata, So  kyouindb  KAKEN_id
Hagiwara, Masatoshi  kyouindb  KAKEN_id
Author's alias: 前田, 信太郎
椎村, 祐樹
浅田, 秀基
平田, 邦生
南後, 恵理子
田中, 信生
豊本, 雅靖
井上, 飛鳥
青木, 淳賢
岩田, 想
萩原, 正敏
Issue Date: Jun-2021
Publisher: American Association for the Advancement of Science (AAAS)
Journal title: Science Advances
Volume: 7
Issue: 24
Thesis number: eabf5325
Abstract: Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.
Description: 脂質受容体の新たな活性化機構を解明 --脂質がまっすぐ伸びて活性化--. 京都大学プレスリリース. 2021-06-10.
Rights: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
DOI(Published Version): 10.1126/sciadv.abf5325
PubMed ID: 34108205
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