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Papers of the Week

Papers: 21 May 2022 - 27 May 2022

Pharmacology/Drug Development

2022 May 24

Cell Discov



Structural insights into the ligand binding and G coupling of serotonin receptor 5-HT.


Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, Ma H, Xu EH, Jiang Y
Cell Discov. 2022 May 24; 8(1):50.
PMID: 35610220.


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