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

Introduction

Psychedelic substances such as LSD, psilocybin and N-benzyl phenethylamine derivatives have a long history of human use and recent clinical interest because of their rapid and sometimes durable therapeutic effects in conditions including depression, anxiety and substance-use disorders. Earlier work implicates agonism of the 5-HT2A serotonin receptor (HTR2A) as essential for their psychedelic effects, but how different hallucinogens engage and stabilise distinct receptor states and downstream signalling cascades remains incompletely understood. Kim and colleagues set out to define molecular details of HTR2A activation by hallucinogens. They determined an active-state structure of HTR2A bound to the selective phenethylamine hallucinogen 25CN-NBOH in complex with an engineered mini-Gαq–βγ heterotrimer stabilised by a single-chain antibody fragment using single-particle cryo-electron microscopy (cryo-EM). To provide structural contrasts, the authors also solved X-ray crystal structures of HTR2A bound to the ergoline hallucinogen LSD and to the inverse agonist methiothepin, enabling comparisons between an active G protein–coupled state and ligand-stabilised inactive-like states. The objective was to identify ligand and receptor features that determine agonism, selectivity and G protein coupling, with implications for structure-guided drug design at HTR2A.