Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
2 papers in the library · 312 citations · publishing 2022-2024
Drugs targeting the human serotonin 2A receptor (5-HT2AR) are used for neuropsychiatric diseases, but many have hallucinogenic effects. Structures of 5-HT2AR complexed with psilocin, LSD, serotonin, and lisuride reveal that serotonin and psilocin show a second binding mode. This insight enabled design of the psychedelic IHCH-7113 and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. These structures provide a foundation for designing safe, nonhallucinogenic psychedelic analogs with therapeutic potential.
LSD dissociates extremely rapidly from the dopamine D1 receptor, driven by the flexibility of extracellular loop 2. Cryo-electron microscopy structures reveal a distinctive binding mode with the ergoline moiety oriented toward transmembrane helix 4. G protein binding stabilizes the extracellular loop 2 conformation, which markedly slows LSD's dissociation rate. These kinetic and structural insights clarify how LSD engages dopamine receptors and how G protein coupling versus β-arrestin coupling is determined, advancing understanding of GPCR dynamics and signal transduction.