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.
Treatments for pain or addiction targeting the κ-opioid receptor often cause hallucinogenic side effects. To understand this, cryo-electron microscopy mapped the receptor's structure with various G-proteins and compounds. These detailed maps uncovered molecular controls for G-protein binding and drug selectivity, showing distinct preferences. This clarifies opioid action, establishing a foundation for developing safer, pathway-selective therapies.