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

Abstract

Abstract5-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.

Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR

“…Notably, replacement with the polar residue threonine appeared to differentially impact the efficacies of setiptiline and mianserin (Emax = 51.2% and 78.3% of 5-HT, respectively), in line with the suggestion of different ligand-receptor interactions from our SIFt analysis. E311 6.55 shows different conformations in the mianserin-and setiptiline-bound structures and previous studies have highlighted the importance of interactions with residues at position 6.55 for ligand specificity (39). According to the SIFt analysis, E311 6.55 forms highly probable apolar interactions with both mianserin and setiptiline during simulation, but it forms an electrostatic interaction with mianserin only, albeit with a very low probability (Fig.…”

Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R

“…E311 6.55 shows different conformations in the mianserin- and setiptiline-bound structures, and previous studies have highlighted the importance of interactions with residues at position 6.55 for ligand specificity ( 39 ). According to the SIFt analysis, E311 6.55 forms highly probable apolar interactions with both mianserin and setiptiline during simulation, but it forms an electrostatic interaction with mianserin only, albeit with a very low probability ( Fig.…”

Biomarker Quantification, Spectroscopic, and Molecular Docking Studies of the Active Compounds Isolated from the Edible Plant Sisymbrium irio L.

“…The X-ray crystal structure (PDB ID: 5U5L) of PPAR-γ in complex with rivoglitazone was resolved to 2.55 Å [10]. Similarly, the X-ray crystal structures of both serotonin receptors, namely 5-HT 1A (PDB ID: 7E2Y) and 5-HT 2A (PDB ID: 6A93), bound with serotonin and risperidone, respectively, were resolved to 3.00 Å [45,46].…”