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Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7T...

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Autores principales: Fatakia, Sarosh N., Costanzi, Stefano, Chow, Carson C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221663/
https://www.ncbi.nlm.nih.gov/pubmed/22132149
http://dx.doi.org/10.1371/journal.pone.0027813
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author Fatakia, Sarosh N.
Costanzi, Stefano
Chow, Carson C.
author_facet Fatakia, Sarosh N.
Costanzi, Stefano
Chow, Carson C.
author_sort Fatakia, Sarosh N.
collection PubMed
description G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection.
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spelling pubmed-32216632011-11-30 Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C. PLoS One Research Article G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection. Public Library of Science 2011-11-21 /pmc/articles/PMC3221663/ /pubmed/22132149 http://dx.doi.org/10.1371/journal.pone.0027813 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Fatakia, Sarosh N.
Costanzi, Stefano
Chow, Carson C.
Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_full Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_fullStr Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_full_unstemmed Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_short Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors
title_sort molecular evolution of the transmembrane domains of g protein-coupled receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221663/
https://www.ncbi.nlm.nih.gov/pubmed/22132149
http://dx.doi.org/10.1371/journal.pone.0027813
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