Lysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.
Docking large libraries of molecules against unrefined AlphaFold2 (AF2) models of the σ2 and serotonin 2A (5-HT2A) receptors produced hit rates and affinities as high as those obtained by docking against experimental structures. These results were achieved despite differences in orthosteric residue conformations between the AF2 models and the experimental structures. A cryo–electron microscopy structure of one potent 5-HT2A ligand identified from AF2 docking showed residue accommodations similar to the AF2 prediction. AF2 models may sample low-energy conformations that differ from experimental structures but remain useful for ligand discovery, extending the reach of structure-based drug design.