Structural basis of psychedelic LSD recognition at dopamine D1 receptor.
Neuron – October 09, 2024
Source: PubMed
Summary
Scientists have revealed how LSD interacts with dopamine receptors in the brain, offering new insights into its effects. Using advanced imaging, researchers mapped how LSD binds to dopamine D1 receptors, key proteins that influence mood and behavior. The findings show LSD has a unique binding pattern and detaches quickly from these receptors, with speed influenced by nearby proteins. This explains part of LSD's complex effects on brain chemistry.
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.