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Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor
Open accessAbstract
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 2A 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.
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“Serotonergic psychedelics act as partial agonists of the serotonin 2A receptor (5-HT2AR) in the brain [7].”
From Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial (2024) · cites this paper as [7]
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Metadata
- Authors
- Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., & Roth, B. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Corresponding author
- Skiniotis, Georgios
- Roth, Bryan L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 182
- Issue
- 6
- Pages
- 1574-1588.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7593816
- OpenAlex
- W3086773311
- Cited by
- 481
- References
- 91
- Citations by year
- 2026: 59 · 2025: 92 · 2024: 86 · 2023: 88 · 2022: 76 · 2021: 72 · 2020: 6
- FWCI
- 19.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institutes of Health (R37DA04567, R01MH112205)
- Argonne National Laboratory (DE-AC02-06CH11357)
- National Institute of General Medical Sciences (AGM-12006)
- National Cancer Institute (ACB-12002, P30CA016086)
- Defense Advanced Research Projects Agency (HR0011-20-2-0029, R35GM122481)
- Office of Science
- U.S. Department of Defense
- National Research Foundation of Korea (2017R1A6A3A03012547)
- University of North Carolina
- U.S. Department of Energy
- Government of South Australia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT2A receptor, hallucinogens, LSD, psilocybin, receptor-G protein complex, methiothepin, inverse agonists, neuropsychiatric disorders
- MeSH terms
- Protein Conformation, alpha-Helical, Animals, Hallucinogens, Humans, Ligands, Lysergic Acid Diethylamide, Methiothepin, Models, Chemical, Mutation, Recombinant Proteins, Serotonin, Gene Expression, Crystallography, X-Ray, Spodoptera, Cryoelectron Microscopy, GTP-Binding Protein alpha Subunits, Gq-G11, Receptor, Serotonin, 5-HT2A, HEK293 Cells
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