8JLZ

ST1936-5HT6R complex

Summary for 8JLZ

• Entry DOI: 10.2210/pdb8jlz/pdb
• EMDB information: 36409
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 152591.12

Authors

Wen, X.,Sun, J. (deposition date: 2023-06-04, release date: 2023-06-28, Last modification date: 2024-10-30)

Primary citation

Pei, Y.,Wen, X.,Guo, S.C.,Yang, Z.S.,Zhang, R.,Xiao, P.,Sun, J.P.
Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6.
Biochem.Biophys.Res.Commun., 671:327-334, 2023

PubMed Abstract: 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.

PubMed: 37327704
DOI: 10.1016/j.bbrc.2023.05.126

Experimental method

ELECTRON MICROSCOPY (3.09 Å)