Structural basis of psychedelic LSD recognition at dopamine D1 receptor.
Neuron October 9, 2024 Luyu Fan, Youwen Zhuang, Hongyu Wu et al. 6 citations
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.