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

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.

SUBMITTER: Tan Y 

PROVIDER: S-EPMC9130316 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature