Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor.

Cell 2020 Sep 17

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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-HT2A 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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

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. Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell. 2020 Sep 17;182(6):1574-1588.e19