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-Structure paper
タイトル | Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes. |
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ジャーナル・号・ページ | Cell, Vol. 184, Issue 4, Page 943-956.e18, Year 2021 |
掲載日 | 2021年2月18日 |
著者 | Peng Xiao / Wei Yan / Lu Gou / Ya-Ni Zhong / Liangliang Kong / Chao Wu / Xin Wen / Yuan Yuan / Sheng Cao / Changxiu Qu / Xin Yang / Chuan-Cheng Yang / Anjie Xia / Zhenquan Hu / Qianqian Zhang / Yong-Hao He / Dao-Lai Zhang / Chao Zhang / Gui-Hua Hou / Huanxiang Liu / Lizhe Zhu / Ping Fu / Shengyong Yang / Daniel M Rosenbaum / Jin-Peng Sun / Yang Du / Lei Zhang / Xiao Yu / Zhenhua Shao / |
PubMed 要旨 | Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five ...Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1. |
リンク | Cell / PubMed:33571432 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.1 - 3.54 Å |
構造データ | EMDB-30392, PDB-7ckw: EMDB-30393, PDB-7ckx: EMDB-30394, PDB-7cky: EMDB-30395, PDB-7ckz: EMDB-30452, PDB-7crh: |
化合物 | ChemComp-G3C: ChemComp-CLR: ChemComp-G3O: ChemComp-G3U: ChemComp-LDP: ChemComp-G4C: ChemComp-GBU: |
由来 |
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キーワード | CELL CYCLE / transmembrane protein / signaling transduction / transduction / complex / signaling complex / cell signaling |