<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Bhosale, Sumedha</style></author><author><style face="normal" font="default" size="100%">Nikte, V. Siddhanta</style></author><author><style face="normal" font="default" size="100%">Sengupta, Durba</style></author><author><style face="normal" font="default" size="100%">Joshi, Manali</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Differential dynamics underlying the Gln27Glu population variant of the beta(2)-adrenergic receptor</style></title><secondary-title><style face="normal" font="default" size="100%">Journal of Membrane Biology</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">beta(2)-Adrenergic receptor</style></keyword><keyword><style  face="normal" font="default" size="100%">G-protein-coupled receptor</style></keyword><keyword><style  face="normal" font="default" size="100%">GPCR</style></keyword><keyword><style  face="normal" font="default" size="100%">molecular dynamics</style></keyword><keyword><style  face="normal" font="default" size="100%">Pharmacogenetics</style></keyword><keyword><style  face="normal" font="default" size="100%">SNP</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2019</style></year><pub-dates><date><style  face="normal" font="default" size="100%">OCT</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">252</style></volume><pages><style face="normal" font="default" size="100%">499-507</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;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.&lt;/p&gt;
</style></abstract><issue><style face="normal" font="default" size="100%">4-5</style></issue><work-type><style face="normal" font="default" size="100%">Article</style></work-type><custom3><style face="normal" font="default" size="100%">&lt;p&gt;Foreign&lt;/p&gt;
</style></custom3><custom4><style face="normal" font="default" size="100%">&lt;p&gt;1.746&lt;/p&gt;
</style></custom4></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Nikte, V. Siddhanta</style></author><author><style face="normal" font="default" size="100%">Sonar, Krushna</style></author><author><style face="normal" font="default" size="100%">Tandale, Aditi</style></author><author><style face="normal" font="default" size="100%">Joshi, Manali</style></author><author><style face="normal" font="default" size="100%">Sengupta, Durba</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Loss of a water-mediated network results in reduced agonist affinity in a beta(2)-adrenergic receptor clinical variant</style></title><secondary-title><style face="normal" font="default" size="100%">Biochimica ET Biophysica Acta-Proteins and Proteomics</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">beta(2)-Adrenergic receptor</style></keyword><keyword><style  face="normal" font="default" size="100%">G protein coupled receptor</style></keyword><keyword><style  face="normal" font="default" size="100%">GPCR</style></keyword><keyword><style  face="normal" font="default" size="100%">molecular dynamics</style></keyword><keyword><style  face="normal" font="default" size="100%">Pharmacogenetics</style></keyword><keyword><style  face="normal" font="default" size="100%">SNP</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2021</style></year><pub-dates><date><style  face="normal" font="default" size="100%">APR</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">1869</style></volume><pages><style face="normal" font="default" size="100%">140605</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;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 ``non-deleterious'' 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.&lt;/p&gt;
</style></abstract><issue><style face="normal" font="default" size="100%">4</style></issue><work-type><style face="normal" font="default" size="100%">Article</style></work-type><custom3><style face="normal" font="default" size="100%">&lt;p&gt;Foreign&lt;/p&gt;
</style></custom3><custom4><style face="normal" font="default" size="100%">3.036
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