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

Psychedelics such as LSD, psilocybin, and related compounds are used recreationally and are being investigated as treatments for depression, anxiety, and substance abuse. Their therapeutic and hallucinogenic effects depend on activating the 5-HT2A serotonin receptor, but the molecular details were unclear. Using cryo-electron microscopy and X-ray crystallography, researchers determined the structures of the 5-HT2A receptor bound to a hallucinogen, LSD, and an inverse agonist. These structures reveal how the receptor interacts with Gαq protein and changes shape when activated. The findings may guide development of more selective drugs for neuropsychiatric disorders.

Study at a glance

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.