2. Academic Validation
  3. Structural basis of psychedelic LSD recognition at dopamine D1 receptor

Structural basis of psychedelic LSD recognition at dopamine D1 receptor

  • Neuron. 2024 Jul 25:S0896-6273(24)00494-X. doi: 10.1016/j.neuron.2024.07.003.
Luyu Fan 1,  Youwen Zhuang 2,  Hongyu Wu 3,  Huiqiong Li 4,  Youwei Xu 2,  Yue Wang 2,  Licong He 3,  Shishan Wang 5,  Zhangcheng Chen 3,  Jianjun Cheng 4,  H Eric Xu 6,  Sheng Wang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: fanluyu2018@sibcb.ac.cn.
  • 2 State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 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.
  • 4 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 5 Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Shandong Second Medical University, Weifang 261021, China.
  • 6 State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Lingang Laboratory, Shanghai 200031, China. Electronic address: eric.xu@simm.ac.cn.
  • 7 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; 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. Electronic address: wangsheng@sibcb.ac.cn.
PMID: 39094559 DOI: 10.1016/j.neuron.2024.07.003
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.

Keywords

DRD1; G protein-coupled receptors; GPCRs; LSD; cryo-EM structures; dopamine D1 receptor; kinetics.

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