02556nas a2200253   4500008004100000022001400041245010300055210007000158260000800228300001200236490000700248520172200255653002301977653003102000653002602031653000902057653001802066653002102084653002002105100002502125700001802150700002002168856011402188       2024                        eng d  a0887-358500aState-dependent dynamics of extramembrane domains in the <i>β</i><sub>2</sub>-adrenergic receptor0 aStatedependent dynamics of extramembrane domains in the iβisub2s  cMAR  a317-3280 v923 a<p>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.</p>
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