한빛사 논문
Kuglae Kim1,7, Tao Che1,6,7, Ouliana Panova2,7, Jeffrey F. DiBerto1, Jiankun Lyu3, Brian E. Krumm1, Daniel Wacker1,5, Michael J. Robertson2, Alpay B. Seven2, David E. Nichols4, Brian K. Shoichet3, Georgios Skiniotis2,*, Bryan L. Roth1,4,8,*
1Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA
2Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
4Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7365, USA
5Present address: Department of Pharmacological Sciences and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
6Present address: Department of Anesthesiology, St. Louis School of Medicine and Center for Clinical Pharmacology, St. Louis College of Pharmacy, Washington University, Saint Louis, MO 63110, USA
7These authors contributed equally
8Lead Contact
*Corresponding author
Abstract
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.
Keywords : GPCR, psychedelic, LSD, sertotonin receptor, signal transduction, structural biology
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