Abstract
Capturing conserved patterns in genes and proteins is important for inferring phenotype prediction and evolutionary analysis. The study is focused on the conserved patterns of the G protein-coupled receptors, an important superfamily of receptors. Olfactory receptors represent more than 2% of our genome and constitute the largest family of G protein-coupled receptors, a key class of drug targets. As no crystallographic structures are available, mechanistic studies rely on the use of molecular dynamic modelling combined with site-directed mutagenesis data. In this paper, we hypothesized that human-mouse orthologs coding for G protein-coupled receptors maintain, at speciation events, shared compositional structures independent, to some extent, of their percent identity as reveals a method based in the categorization of nucleotide triplets by their gross composition. The data support the consistency of the hypothesis, showing in ortholog G protein-coupled receptors the presence of emergent shared compositional structures preserved at speciation events. An extreme bias in synonymous codon usage is observed in both the conserved and non-conserved regions of many of these receptors that could be potentially relevant in codon optimization studies. The analysis of their compositional structures would help to design new evolutionary based strategies for rational mutations that would aid to understand the characteristics of individual G protein-coupled receptors, their subfamilies and the role in many physiological and pathological processes, supplying new possible drug targets.
Highlights
Gprotein-coupled receptors (GPCRs) are integral membrane proteins used by cells to convert extracellular signals into intracellular responses
The aim of the study was to identify novel compositional structures interspersed in GPCRs that could be useful for site-directed mutagenesis and potentially relevant in seeking new drug targets
We investigated the emergent compositional structures shared by human-mouse ortholog GPCRs to study whether there are evidences of constraints for variability
Summary
Gprotein-coupled receptors (GPCRs) are integral membrane proteins used by cells to convert extracellular signals into intracellular responses. More than 50% of GPCRs are orphan receptors [5, 6] sharing common structural motifs in which seven transmembrane helices are connected to three extracellular loops and to three intracellular loops (see Figure 1A), being activated by a variety of external stimuli [7]. They are targets for the bulk of therapeutic drugs, playing important roles in many biological processes [8, 9]. The poor functional heterologous expression, the post-translational modifications, the high flexibility, and the low stability in detergent hampering the understanding of the molecular mechanism of the OR
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