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

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are medi-ated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and sim-ilarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer -free, Gq-protein-coupled, and b-arrestin-1-coupled states. These structures provide distinct signaling snap-shots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

Automated summary

This study determines the binding of LSD to HTR2B receptors in different states using cryo-EM structures, providing molecular insights into the mechanism of LSD's psychedelic effects and accelerating the discovery of novel psychedelic drugs.