Structural basis of psychedelic LSD recognition at dopamine D1 receptor.
Luyu Fan, Youwen Zhuang, Hongyu Wu, Huiqiong Li, Youwei Xu, Yue Wang, Licong He, Shishan Wang, Zhangcheng Chen, Jianjun Cheng, H Eric Xu, Sheng Wang
Neuron October 9, 2024 DOI: 10.1016/j.neuron.2024.07.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural and kinetic study Peer reviewed |
|---|---|
| Topics | LSD |
| Keywords | Psychedelics LSD Dopamine receptors drd1 Gpcrs G protein-coupled receptors Cryo-em structures Dopamine d1 receptor Kinetics Molecular biology |
| Citations | 6 |
| Key points | LSD has an exceptionally rapid dissociation rate from the dopamine D1 receptor, which is slowed by G protein stabilization of extracellular loop 2. |
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.