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TitleStructural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6.
Journal, issue, pagesBiochem Biophys Res Commun, Vol. 671, Page 327-334, Year 2023
Publish dateJun 5, 2023
AuthorsYuan Pei / Xin Wen / Sheng-Chao Guo / Zhi-Shuai Yang / Ru Zhang / Peng Xiao / Jin-Peng Sun /
PubMed AbstractThe serotonin receptor 5-HTR is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various ...The serotonin receptor 5-HTR is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various psychiatric disorders. Selective activation of 5-HTR promotes neural stem cell regeneration activity. As a 5-HTR selective agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N, N-dimethylethanolamine (ST1936) has been widely used to investigate the functions of the 5-HTR. The molecular mechanism of how ST1936 is recognized by 5-HTR and how it effectively couples with Gs remain unclear. Here, we reconstituted the ST1936-5-HTR-Gs complex in vitro and solved its cryo-electron microscopy structure at 3.1 Å resolution. Further structural analysis and mutational studies facilitated us to identify the residues of the Y310 and "toggle switch" W281 of the 5-HTR contributed to the higher efficacy of ST1936 compared with 5-HT. By uncovering the structural foundation of how 5-HTR specifically recognizes agonists and elucidating the molecular process of G protein activation, our discoveries offer valuable insights and pave the way for the development of promising 5-HTR agonists.
External linksBiochem Biophys Res Commun / PubMed:37327704
MethodsEM (single particle)
Resolution3.09 Å
Structure data

36409

8jlz

EMDB-36409, PDB-8jlz:
ST1936-5HT6R complex
Method: EM (single particle) / Resolution: 3.09 Å

Chemicals

ChemComp-UQL:
2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine

Source
  • homo sapiens (human)
  • camelus bactrianus (Bactrian camel)
KeywordsMEMBRANE PROTEIN / GPCR

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