2. Academic Validation
  3. Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6

Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6

  • Biochem Biophys Res Commun. 2023 Sep 3:671:327-334. doi: 10.1016/j.bbrc.2023.05.126.
Yuan Pei 1,  Xin Wen 2,  Sheng-Chao Guo 2,  Zhi-Shuai Yang 2,  Ru Zhang 2,  Peng Xiao 2,  Jin-Peng Sun 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Surface Physics, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education) and Collaborative Innovation Center of Advanced Microstructures, Fudan University, Shanghai, 200433, China; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 3 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 37327704 DOI: 10.1016/j.bbrc.2023.05.126
Abstract

The serotonin receptor 5-HT6R 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-HT6R promotes neural stem cell regeneration activity. As a 5-HT6R 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-HT6R. The molecular mechanism of how ST1936 is recognized by 5-HT6R and how it effectively couples with Gs remain unclear. Here, we reconstituted the ST1936-5-HT6R-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 Y3107.43 and "toggle switch" W2816.48 of the 5-HT6R contributed to the higher efficacy of ST1936 compared with 5-HT. By uncovering the structural foundation of how 5-HT6R 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-HT6R agonists.

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