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TitleStructural basis of psychedelic LSD recognition at dopamine D receptor.
Journal, issue, pagesNeuron, Vol. 112, Issue 19, Page 3295-33310.e8, Year 2024
Publish dateOct 9, 2024
AuthorsLuyu Fan / Youwen Zhuang / Hongyu Wu / Huiqiong Li / Youwei Xu / Yue Wang / Licong He / Shishan Wang / Zhangcheng Chen / Jianjun Cheng / H Eric Xu / Sheng Wang /
PubMed AbstractUnderstanding 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 ...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 D 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.
External linksNeuron / PubMed:39094559
MethodsEM (single particle)
Resolution3.0 - 3.57 Å
Structure data

36710

8jxr

EMDB-36710, PDB-8jxr:
Structure of nanobody-bound DRD1_LSD complex
Method: EM (single particle) / Resolution: 3.57 Å

36711

8jxs

EMDB-36711, PDB-8jxs:
Structure of nanobody-bound DRD1_PF-6142 complex
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-7LD:
(8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide


ChemComp, No image

ChemComp-V6X:
Unknown entry

Source
  • homo sapiens (human)
  • escherichia coli o157:h7 (bacteria)
  • mus musculus (house mouse)
  • streptococcus sp. 'group g' (bacteria)
  • Escherichia coli (E. coli)
  • staphylococcus aureus (bacteria)
  • staphylococcus aureus subsp. aureus mu50 (bacteria)
  • escherichia coli k-12 (bacteria)
KeywordsMEMBRANE PROTEIN / GPCR / DRD1 / LSD / PF-6142

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