Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor
UNC Libraries – June 07, 2024
Source: OpenAlex
Summary
The molecular mechanism of hallucinogens like LSD and psilocybin is now clearer. Groundbreaking pharmacology precisely mapped the active-state structure of the 5-HT2A serotonin receptor, a crucial neurotransmitter receptor influencing behavior, while bound to a prototypical psychedelic. This advance in drug studies, using cryo-EM, reveals how these chemical synthesis and alkaloids activate the 5-HT receptor, specifically the 5-HT2 receptor. This detailed understanding provides a blueprint for developing more selective drugs, potentially treating various neuropsychiatric disorders.
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. © 2020 Elsevier Inc.; Roth et al. reveal structurally how psychedelics, including LSD, psilocin, mescaline, and various N-BOH analogs, mediate their therapeutic and hallucinogenic effects by binding to and activating their molecular target, the serotonin (5-HT) 2A receptor coupled with G-protein Gαq.