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

  • Cell Discov. 2022 May 24;8(1):50. doi: 10.1038/s41421-022-00412-3.
Yangxia Tan  #  1  2 ,  Peiyu Xu  #  1  3 ,  Sijie Huang  #  1  2 ,  Gong Yang  4 ,  Fulai Zhou  1  3 ,  Xinheng He  1  3 ,  Honglei Ma  5 ,  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. [email protected].
  • 7. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 8. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 9. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 10. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 11. Lingang Laboratory, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 35610220 DOI: 10.1038/s41421-022-00412-3
Abstract

5-hydroxytryptamine receptor 5A (5-HT5A) belongs to the 5-HT Receptor family and signals through the Gi/o protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT5A is the only Gi/o-coupled 5-HT Receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and Gi/o coupling for 5-HT5A. Here we report a cryo-electron microscopy structure of the 5-HT5A-Gi 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 Gi/o-coupled 5-HT receptors. In addition, 5-HT5A shows an overall conserved Gi protein coupling mode compared with Other Gi/o-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of Gi/o-coupled 5-HT receptors and offer a template for the design of 5-HT5A-selective drugs.