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Structure paper

TitleSignaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.
Journal, issue, pagesNeuron, Vol. 110, Issue 19, Page 3154-33167.e7, Year 2022
Publish dateOct 5, 2022
AuthorsCan Cao / Ximena Barros-Álvarez / Shicheng Zhang / Kuglae Kim / Marc A Dämgen / Ouliana Panova / Carl-Mikael Suomivuori / Jonathan F Fay / Xiaofang Zhong / Brian E Krumm / Ryan H Gumpper / Alpay B Seven / Michael J Robertson / Nevan J Krogan / Ruth Hüttenhain / David E Nichols / Ron O Dror / Georgios Skiniotis / Bryan L Roth /
PubMed AbstractSerotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug ...Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT serotonin receptor (HTR2A), the 5-HT serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.
External linksNeuron / PubMed:36087581 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.3 Å
Structure data

25401

7srq

EMDB-25401, PDB-7srq:
5-HT2B receptor bound to LSD obtained by cryo-electron microscopy (cryoEM)
Method: EM (single particle) / Resolution: 2.7 Å

25402

7srr

EMDB-25402, PDB-7srr:
5-HT2B receptor bound to LSD in complex with heterotrimeric mini-Gq protein obtained by cryo-electron microscopy (cryoEM)
Method: EM (single particle) / Resolution: 2.9 Å

25403

7srs

EMDB-25403, PDB-7srs:
5-HT2B receptor bound to LSD in complex with beta-arrestin1 obtained by cryo-electron microscopy (cryoEM)
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / 5-HT2B receptor / serotonin receptor / GPCR / Lysergic acid diethylamide / LSD / cryoEM / G protein / beta-arrestin1 / arrestin

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