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

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.

1 aTandale, Aditi1 aJoshi, Manali1 aSengupta, Durba uhttps://library.ncl.res.in/content/structural-insights-and-functional-implications-inter-individual-variability-beta202556nas a2200253 4500008004100000022001400041245010300055210007000158260000800228300001200236490000700248520172200255653002301977653003102000653002602031653000902057653001802066653002102084653002002105100002502125700001802150700002002168856011402188 2024 eng d a0887-358500aState-dependent dynamics of extramembrane domains in the β2-adrenergic receptor0 aStatedependent dynamics of extramembrane domains in the iβisub2s cMAR a317-3280 v923 a

G protein-coupled receptors (GPCRs) are membrane-bound signaling proteins that play an essential role in cellular signaling processes. Due to their intrinsic function of transmitting internal signals in response to external cues, these receptors are adapted to be highly dynamic in nature. The beta(2)-adrenergic receptor (beta 2AR) is a representative member of the family that has been extensively analyzed in terms of its structure and activation. Although the structure of the transmembrane domain has been characterized in the different functional states of the receptor, the conformational dynamics of the extramembrane domains, especially the intrinsically disordered regions are still emerging. In this study, we analyze the state-dependent dynamics of extramembrane domains of beta(2)AR using atomistic molecular dynamics simulations. We introduce a parameter, the residue excess dynamics that allows us to better quantify receptor dynamics. Using this measure, we show that the dynamics of the extramembrane domains are sensitive to the receptor state. Interestingly, the ligand-bound intermediate R' state shows the maximal dynamics compared to either the active R*G or inactive R states. Ligand binding appears to be correlated with high residue excess dynamics that are dampened upon G protein coupling. The intracellular loop-3 (ICL3) domain has a tendency to flip towards the membrane upon ligand binding, which could contribute to receptor ``priming.'' We highlight an important ICL1-helix-8 interplay that is broken in the ligand-bound state but is retained in the active state. Overall, our study highlights the importance of characterizing the functional dynamics of the GPCR loop domains.

10aallosteric pathway10abeta-2 adrenergic receptor10aextramembrane domains10aGPCR10aloop dynamics10aprotein dynamics10aprotein network1 aNikte, Siddhanta, V.1 aJoshi, Manali1 aSengupta, Durba uhttps://library.ncl.res.in/content/state-dependent-dynamics-extramembrane-domains-%CE%B22-adrenergic-receptor