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-Structure paper
タイトル | Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor. |
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ジャーナル・号・ページ | Cell, Vol. 182, Issue 6, Page 1574-1588.e19, Year 2020 |
掲載日 | 2020年9月17日 |
著者 | Kuglae Kim / Tao Che / Ouliana Panova / Jeffrey F DiBerto / Jiankun Lyu / Brian E Krumm / Daniel Wacker / Michael J Robertson / Alpay B Seven / David E Nichols / Brian K Shoichet / Georgios Skiniotis / Bryan L Roth / |
PubMed 要旨 | Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many ...Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders. |
リンク | Cell / PubMed:32946782 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.36 Å |
構造データ | EMDB-21669, PDB-6wha: |
化合物 | ChemComp-U0G: |
由来 |
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キーワード | MEMBRANE PROTEIN/IMMUNE SYSTEM / 5HT2A / G protein / 25-CN-NBOH / GPCR / cryo-EM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex |