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.
Highlights
Gprotein-coupled receptors (GPCRs) constitute a diverse superfamily of integral membrane proteins involved in intercellular signal transduction
We have found that class A GPCR subgroups that are naturally activated by small molecules possessed strong negative selection in the key positions
The selection pressure at the key positions is more likely to be stronger than the rest of the TM positions in small molecule receptors
Summary
Gprotein-coupled receptors (GPCRs) constitute a diverse superfamily of integral membrane proteins involved in intercellular signal transduction. Their genes are expressed in almost all eukaryotes [1,2,3,4,5]. GPCRs are the largest superfamily of integral membrane proteins in humans. About half of the GPCRs in the human genome are non-olfactory receptors [6,7,8]. These receptors mediate vital physiological functions and are a major target for pharmaceutical interventions [9,10]. Class A receptors bind different natural ligands that range from small-molecules such as ADP to larger ones such as neuropeptides or chemokines
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