Evolutionary association of receptor-wide amino acids with G protein coupling selectivity in aminergic GPCRs
This repository contains the suplementary files and codes that were used for the analyses of the paper "Evolutionary association of receptor-wide amino acids with G protein coupling selectivity in aminergic GPCRs"
Authors: Berkay Selçuk, İsmail Erol, Serdar Durdağı, Ogun Adebali
Contact for scripts and supplementary data: bselcuk@sabanciuniv.edu
G protein-coupled receptors (GPCRs) induce signal transduction pathways through coupling to four main subtypes of G proteins (Gs, Gi, Gq, G12/13), selectively. However, G protein selective activation mechanisms and residual determinants in GPCRs have remained obscure. Herein, we performed an extensive phylogenetic analysis and identified specifically conserved residues for the aminergic receptors having similar coupling profiles in each aminergic receptor. By integrating our methodology of differential evolutionary conservation of G protein-specific amino acids with structural analyses, we identified selective specific activation networks for Gs, Gi1, Go, and Gq. To validate that these networks could determine coupling selectivity we further analyzed Gs specific activation network and its association with Gs selectivity. network and associated it with the larger TM6 tilt which is a signature of Gs-coupled receptors. Through molecular dynamics simulations, we showed that previously uncharacterized Glycine at position 7x41 plays an important role in both receptor activation and Gs coupling selectivity by inducing a larger TM6 movement. Finally, we gathered our results into a comprehensive model of G protein selectivity called “sequential switches of activation” describing three main molecular switches controlling GPCR activation: ligand binding, G protein selective activation mechanisms, and G protein contact.