02174nas a2200181 4500008004100000022001400041245013500055210006900190260009100259300001300350490000700363520141300370100002001783700002101803700002001824700001801844856013001862 2014 eng d a1553-734X00aMolecular Insights into the dynamics of pharmacogenetically important N-terminal variants of the human beta(2)-adrenergic receptor0 aMolecular Insights into the dynamics of pharmacogenetically impo a1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USAbPUBLIC LIBRARY SCIENCEcDEC ae10040060 v103 a

The human beta(2)-adrenergic receptor (beta(2)AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, beta(2)AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of beta(2)AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the beta(2)AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N-terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N-terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients.

1 aShahane, Ganesh1 aParsania, Chirag1 aSengupta, Durba1 aJoshi, Manali uhttp://library.ncl.res.in/content/molecular-insights-dynamics-pharmacogenetically-important-n-terminal-variants-human-beta2-002197nas a2200241 4500008004100000022001400041245013700055210006900192260000800261300001200269490000800281520136100289653002801650653001501678653001001693653002501703653001501728100002201743700001801765700002001783700002801803856012401831 2018 eng d a0009-308400aMembrane-induced organization and dynamics of the N-terminal domain of chemokine receptor CXCR1: insights from atomistic simulations0 aMembraneinduced organization and dynamics of the Nterminal domai cJAN a142-1480 v2103 a

The CXC chemokine receptor 1 (CXCR1) is an important member of the G protein-coupled receptor (GPCR) family in which the extracellular N-terminal domain has been implicated in ligand binding and selectivity. The structure of this domain has not yet been elucidated due to its inherent dynamics, but experimental evidence points toward membrane-dependent organization and dynamics. To gain molecular insight into the interaction of the N-terminal domain with the membrane bilayer, we performed a series of microsecond time scale atomistic simulations of the N-terminal domain of CXCR1 in the presence and absence of POPC bilayers. Our results show that the peptide displays a high propensity to adopt a beta-sheet conformation in the presence of the membrane bilayer. The interaction of the peptide with the membrane bilayer was found to be transient in our simulations. Interestingly, a scrambled peptide, containing the same residues in a randomly varying sequence, did not exhibit membrane-modulated structural dynamics. These results suggest that sequence-dependent electrostatics, modulated by the membrane, could play an important role in folding of the N-terminal domain. We believe that our results reinforce the emerging paradigm that cellular membranes could be important modulators of function of G protein-coupled receptors such as CXCR1.

10aAll atom MD simulations10abeta-sheet10aCXCR110aMembrane interaction10aN-terminal1 aKharche, Shalmali1 aJoshi, Manali1 aSengupta, Durba1 aChattopadhyay, Amitabha uhttp://library.ncl.res.in/content/membrane-induced-organization-and-dynamics-n-terminal-domain-chemokine-receptor-cxcr102261nas a2200241 4500008004100000022001400041245009500055210006900150260000800219490000800227520149500235653001201730653002501742653001701767653002301784653002401807653001401831100001701845700000501862700002201867700001801889856011201907 2021 eng d a0022-263100aMolecular characterization of the beta(2)-like octopamine receptor of helicoverpa armigera0 aMolecular characterization of the beta2like octopamine receptor  cJUN0 v2543 a

Helicoverpa armigera is a devastating polyphagous and cosmopolitan crop pest. There are reports of this insect being resistant to a variety of pesticides raising concern worldwide. The Octopamine (OA) binding beta(2)-like receptor (OAR), a GPCR, is widely distributed in the nervous system of the insect and plays essential roles in the physiology and development and thus is an important target for insecticides. Yet, the molecular characterization of the H. armigera OAR (HarmOAR) and rational design of compounds based on this receptor is lacking. As a first step, we performed multiple sequence alignment of all insect OARs, which revealed that the sequences contained all conserved class A GPCR motifs. Phylogenetic studies showed clade-specific variations in the protein sequences primarily arising owing to differences in the ICL3 loop region. Further, a structural model of HarmOAR was built using the inactive human beta(2)AR as a template. 0.9 mu s atomistic simulations revealed conserved inter helical contacts and water molecules of HarmOAR. The detailed binding of octopamine was studied using molecular docking and 0.3 mu s atomistic simulations. Twenty-two insecticides active against octopamine receptors of other insects were compiled and docked to HarmOAR followed by rescoring with binding free energies to prioritize them for H. armigera. Our study suggests alpha-terpineol to be a good candidate as an insecticide or insect repellent for Helicoverpa armigera.

10adocking10aHelicoverpa armigera10aInsecticides10amolecular dynamics10aOctopamine receptor10aPhylogeny1 aGujar, Nidhi1 a1 aJoshi, Rakesh, S.1 aJoshi, Manali uhttp://library.ncl.res.in/content/molecular-characterization-beta2-octopamine-receptor-helicoverpa-armigera02059nas a2200169 4500008004100000020001800041245011900059210006900178260000800247300001200255490000800267520142900275100001801704700002101722700002001743856012601763 2022 eng d a978032398895700aMolecular determinants of GPCR pharmacogenetics: deconstructing the population variants in β2-adrenergic receptor0 aMolecular determinants of GPCR pharmacogenetics deconstructing t cJAN a361-3960 v1283 a

G protein-coupled receptors (GPCRs) are membrane proteins that play a central role in cell signaling and constitute one of the largest classes of drug targets. The molecular mechanisms underlying GPCR function have been characterized by several experimental and computational methods and provide an understanding of their role in physiology and disease. Population variants arising from nsSNPs affect the native function of GPCRs and have been implicated in differential drug response. In this chapter, we provide an overview on GPCR structure and activation, with a special focus on the β2-adrenergic receptor (β2-AR). First, we discuss the current understanding of the structural and dynamic features of the wildtype receptor. Subsequently, the population variants identified in this receptor from clinical and large-scale genomic studies are described. We show how computational approaches such as bioinformatics tools and molecular dynamics simulations can be used to characterize the variant receptors in comparison to the wildtype receptor. In particular, we discuss three examples of clinically important variants and discuss how the structure and function of these variants differ from the wildtype receptor at a molecular level. Overall, the chapter provides an overview of structure and function of GPCR variants and is a step towards the study of inter-individual differences and personalized medicine.

1 aJoshi, Manali1 aNikte, Siddhanta1 aSengupta, Durba uhttp://library.ncl.res.in/content/molecular-determinants-gpcr-pharmacogenetics-deconstructing-population-variants-%CE%B22