Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)

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)-cou...

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Autores principales: Tan, Yangxia, Xu, Peiyu, Huang, Sijie, Yang, Gong, Zhou, Fulai, He, Xinheng, Ma, Honglei, Xu, H. Eric, Jiang, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130316/
https://www.ncbi.nlm.nih.gov/pubmed/35610220
http://dx.doi.org/10.1038/s41421-022-00412-3
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author Tan, Yangxia
Xu, Peiyu
Huang, Sijie
Yang, Gong
Zhou, Fulai
He, Xinheng
Ma, Honglei
Xu, H. Eric
Jiang, Yi
author_facet Tan, Yangxia
Xu, Peiyu
Huang, Sijie
Yang, Gong
Zhou, Fulai
He, Xinheng
Ma, Honglei
Xu, H. Eric
Jiang, Yi
author_sort Tan, Yangxia
collection PubMed
description 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.
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spelling pubmed-91303162022-05-26 Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A) Tan, Yangxia Xu, Peiyu Huang, Sijie Yang, Gong Zhou, Fulai He, Xinheng Ma, Honglei Xu, H. Eric Jiang, Yi Cell Discov Article 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. Springer Nature Singapore 2022-05-24 /pmc/articles/PMC9130316/ /pubmed/35610220 http://dx.doi.org/10.1038/s41421-022-00412-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tan, Yangxia
Xu, Peiyu
Huang, Sijie
Yang, Gong
Zhou, Fulai
He, Xinheng
Ma, Honglei
Xu, H. Eric
Jiang, Yi
Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title_full Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title_fullStr Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title_full_unstemmed Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title_short Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A)
title_sort structural insights into the ligand binding and g(i) coupling of serotonin receptor 5-ht(5a)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130316/
https://www.ncbi.nlm.nih.gov/pubmed/35610220
http://dx.doi.org/10.1038/s41421-022-00412-3
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