Structural insights and functional implications of inter-individual variability in β 2 -adrenergic receptor

Abstract

The human β 2 -adrenergic receptor (β 2 AR) belongs to the G protein-coupled receptor (GPCR) family and due to its central role in bronchodilation, is an important drug target. The inter-individual variability in β 2 AR has been implicated in disease susceptibility and differential drug response. In this work, we identified nine potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) using a consensus approach. The deleterious nsSNPs were found to cluster near the ligand binding site and towards the G-protein binding site. To assess their molecular level effects, we built structural models of these receptors and performed atomistic molecular dynamics simulations. Most notably, in the Phe290Ser variant we observed the rotameric flip of Trp286 6.48, a putative activation switch that has not been reported in β 2 AR thus far. In contrast, the variant Met82Lys was found to be the most detrimental to epinephrine binding. Additionally, a few of the nsSNPs were seen to cause perturbations to the lipid bilayer, while a few lead to differences at the G-protein coupling site. We are thus able to classify the variants as ranging from activating to damaging, prioritising them for experimental studies.