Structural insights into the ligand binding and Gi coupling of serotonin receptor 5-HT5A

Yangxia Tan; Peiyu Xu; Sijie Huang; Gong Yang; Fulai Zhou; Xinheng He; Honglei Ma; H Eric Xu; Yi Jiang

doi:10.1038/s41421-022-00412-3

Structural insights into the ligand binding and G_i coupling of serotonin receptor 5-HT_5A

Cell Discov. 2022 May 24;8(1):50. doi: 10.1038/s41421-022-00412-3.

Authors

Yangxia Tan^#^{1

2}, Peiyu Xu^#^{1

3}, Sijie Huang^#^{1

2}, Gong Yang⁴, Fulai Zhou^{1

3}, Xinheng He^{1

3}, Honglei Ma⁵, H Eric Xu^{6

7

8}, Yi Jiang^{9

10

11}

Affiliations

¹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
⁵ State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, China.
⁶ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
⁹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. yijiang@simm.ac.cn.
¹⁰ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yijiang@simm.ac.cn.
¹¹ Lingang Laboratory, Shanghai, China. yijiang@simm.ac.cn.

^# Contributed equally.

Abstract

5-hydroxytryptamine receptor 5A (5-HT_5A) belongs to the 5-HT receptor family and signals through the G_i/o protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT_5A is the only G_i/o-coupled 5-HT receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and G_i/o coupling for 5-HT_5A. Here we report a cryo-electron microscopy structure of the 5-HT_5A-G_i complex bound to 5-Carboxamidotryptamine (5-CT). Combined with functional analysis, this structure reveals the 5-CT recognition mechanism and identifies the receptor residue at 6.55 as a determinant of the 5-CT selectivity for G_i/o-coupled 5-HT receptors. In addition, 5-HT_5A shows an overall conserved G_i protein coupling mode compared with other G_i/o-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of G_i/o-coupled 5-HT receptors and offer a template for the design of 5-HT_5A-selective drugs.