@article {46342, title = {Differential dynamics underlying the Gln27Glu population variant of the beta(2)-adrenergic receptor}, journal = {Journal of Membrane Biology}, volume = {252}, year = {2019}, month = {OCT}, pages = {499-507}, type = {Article}, abstract = {

The beta (2)-adrenergic receptor (beta (2)AR) is a membrane-bound G-protein-coupled receptor and an important drug target for asthma. Clinical studies report that the population variant Gln27Glu is associated with a differential response to common asthma drugs, such as albuterol, isoproterenol and terbutaline. Interestingly, the 27th amino acid is positioned on the N-terminal region that is the most flexible and consequently the least studied part of the receptor. In this study, we probe the molecular origin of the differential drug binding by performing structural modeling and simulations of the wild-type (Gln) and variant (Glu) receptors followed by ensemble docking with the ligands, albuterol, isoproterenol and terbutaline. In line with clinical studies, the ligands were observed to interact preferentially with the Glu variant. Our results indicate that the Glu residue at the 27th position perturbs the network of electrostatic interactions that connects the N-terminal region to the binding site in the wild-type receptor. As a result, the Glu variant is observed to bind better to the three ligands tested in this study. Our study provides a structural basis to explain the variable drug response associated with the 27th position polymorphism in the beta (2)AR and is a starting step to identify genotype-specific therapeutics.

}, keywords = {beta(2)-Adrenergic receptor, G-protein-coupled receptor, GPCR, molecular dynamics, Pharmacogenetics, SNP}, issn = {0022-2631}, doi = {10.1007/s00232-019-00093-2}, author = {Bhosale, Sumedha and Nikte, V. Siddhanta and Sengupta, Durba and Joshi, Manali} } @article {47034, title = {Loss of a water-mediated network results in reduced agonist affinity in a beta(2)-adrenergic receptor clinical variant}, journal = {Biochimica ET Biophysica Acta-Proteins and Proteomics}, volume = {1869}, year = {2021}, month = {APR}, pages = {140605}, type = {Article}, abstract = {

The beta(2)-adrenergic receptor (beta(2)AR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly {\textquoteleft}{\textquoteleft}non-deleterious{\textquoteright}{\textquoteright} substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response. We are able to identify hydration sites in the transmembrane domain that are essential to maintain the integrity of the binding site but are absent in the variant. The loss of these hydration sites in the variant correlates with perturbations in the intra-protein interaction network and rearrangements in the orthosteric ligand binding site. In conjunction, we observe an altered binding and reduced free energy of a series of agonists, in line with experimental trends. Our work identifies a functional allosteric pathway connected by specific hydration sites in beta(2)AR that has not been reported before and provides insight into water-mediated networks in GPCRs in general. Overall, the work is one of the first step towards developing variant-specific potent and selective agonists.

}, keywords = {beta(2)-Adrenergic receptor, G protein coupled receptor, GPCR, molecular dynamics, Pharmacogenetics, SNP}, issn = {1570-9639}, doi = {10.1016/j.bbapap.2021.140605}, author = {Nikte, V. Siddhanta and Sonar, Krushna and Tandale, Aditi and Joshi, Manali and Sengupta, Durba} } @article {48970, title = {State-dependent dynamics of extramembrane domains in the β2-adrenergic receptor}, journal = {Proteins- Structure Function and Bioinformatics }, volume = {92}, year = {2024}, month = {MAR}, pages = {317-328}, type = {Article}, abstract = {

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{\textquoteright} 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 {\textquoteleft}{\textquoteleft}priming.{\textquoteright}{\textquoteright} 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.

}, keywords = {allosteric pathway, beta-2 adrenergic receptor, extramembrane domains, GPCR, loop dynamics, protein dynamics, protein network}, issn = {0887-3585}, doi = {10.1002/prot.26613}, author = {Nikte, Siddhanta V. and Joshi, Manali and Sengupta, Durba} }