01950nas a2200169   4500008004100000022001400041245011500055210006900170260009000239300001000329490000600339520125600345100001901601700001801620700002001638856012201658       2016                        eng d  a2045-232200aStructural insights and functional implications of inter-individual variability in beta(2)-adrenergic receptor0 aStructural insights and functional implications of interindividu  aMACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLANDbNATURE PUBLISHING GROUPcAPR  a243790 v63 a<p>The human beta(2)-adrenergic receptor (beta(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 beta(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 beta(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.</p>1 aTandale, Aditi1 aJoshi, Manali1 aSengupta, Durba  uhttps://library.ncl.res.in/content/structural-insights-and-functional-implications-inter-individual-variability-beta2