Journal
CELL
Volume 182, Issue 6, Pages 1574-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.08.024
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Funding
- National Cancer Institute [P30CA016086, ACB12002]
- National Institute of General Medical Sciences [AGM-12006]
- DOE Office of Science [DE-AC02-06CH11357]
- Korea Research Foundation (KRF) [2017R1A6A3A03012547]
- NIH [R37DA04567, R01MH112205, R35GM122481]
- DARPA [HR0011-20-2-0029]
- National Research Foundation of Korea [2017R1A6A3A03012547] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 G alpha q 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-G alpha q 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.
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