Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Introduction

Lysergic acid diethylamide (LSD) is a broadly acting psychedelic that binds many biogenic amine G-protein-coupled receptors (GPCRs), with primary psychedelic effects attributed to 5-HT2A (HTR2A). However, LSD also activates 5-HT2B (HTR2B), and chronic activation of HTR2B is implicated in drug-induced valvular heart disease. GPCRs of the 5-HT2 family signal through both Gq proteins and b-arrestins, and some ligands stabilise receptor conformations that preferentially engage one downstream pathway over another (biased signaling). Despite prior X-ray structures of LSD-bound HTR2A and HTR2B in transducer-free states, the molecular bases for differential engagement of G proteins versus arrestins by the same ligand remain incompletely understood. To address this gap, Cao and colleagues determined cryo-electron microscopy (cryo-EM) structures of LSD-bound HTR2B in three states: transducer-free, Gq-coupled, and b-arrestin-1-coupled. Their aim was to capture conformational snapshots that reveal how the same ligand (LSD) can drive distinct transducer-specific receptor conformations and to combine structural work with functional assays, mass spectrometry and molecular dynamics (MD) to link structural features to signalling outcomes.