Structural basis of psychedelic LSD recognition at dopamine D1 receptor.

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.

Study at a glance

Abstract

Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's interactions with serotonin 2A and 2B receptors, its behavior on other targets, including dopamine receptors, has remained elusive. Here, we present cryo-EM structures of LSD/PF6142-bound dopamine D1 receptor (DRD1)-legobody complexes, accompanied by a β-arrestin-mimicking nanobody, NBA3, shedding light on the determinants of G protein coupling versus β-arrestin coupling. Structural analysis unveils a distinctive binding mode of LSD in DRD1, particularly with the ergoline moiety oriented toward TM4. Kinetic investigations uncover an exceptionally rapid dissociation rate of LSD in DRD1, attributed to the flexibility of extracellular loop 2 (ECL2). Moreover, G protein can stabilize ECL2 conformation, leading to a significant slowdown in ligand's dissociation rate. These findings establish a solid foundation for further exploration of G protein-coupled receptor (GPCR) dynamics and their relevance to signal transduction.