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

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
6
Issue
11
Identifiers
DOI: 10.1371/journal.pone.0027813
Keywords
  • Research Article
  • Biology
  • Biochemistry
  • Biomacromolecule-Ligand Interactions
  • Computational Biology
  • Sequence Analysis
  • Evolutionary Biology
  • Evolutionary Processes
  • Coevolution
  • Natural Selection
  • Genomics
  • Molecular Cell Biology
  • Signal Transduction
  • Signaling In Cellular Processes
  • G-Protein Signaling
  • Chemistry
  • Computational Chemistry
Disciplines
  • Biology
  • Pharmacology

Abstract

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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