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-Structure paper
タイトル | Structural genomics of the human dopamine receptor system. |
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ジャーナル・号・ページ | Cell Res, Vol. 33, Issue 8, Page 604-616, Year 2023 |
掲載日 | 2023年5月23日 |
著者 | Peiyu Xu / Sijie Huang / Brian E Krumm / Youwen Zhuang / Chunyou Mao / Yumu Zhang / Yue Wang / Xi-Ping Huang / Yong-Feng Liu / Xinheng He / Huadong Li / Wanchao Yin / Yi Jiang / Yan Zhang / Bryan L Roth / H Eric Xu / |
PubMed 要旨 | The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to ...The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system. |
リンク | Cell Res / PubMed:37221270 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.7 - 3.2 Å |
構造データ | EMDB-35683, PDB-8irr: EMDB-35684, PDB-8irs: EMDB-35685, PDB-8irt: EMDB-35686, PDB-8iru: EMDB-35687, PDB-8irv: |
化合物 | ChemComp-R5F: ChemComp-CLR: ChemComp-HOH: ChemComp-PLM: |
由来 |
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キーワード | MEMBRANE PROTEIN / Dopamine / Dopamine receptor / GPCR / D1R / Gs / Rotigotine / Parkinson's disease / Restless legs syndrome / D2R / Gi / Polypharmacology Parkinson's disease / D3R / D4R / D5R |