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000008401 0247_ $$2DOI$$a10.1002/pro.285
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000008401 084__ $$2WoS$$aBiochemistry & Molecular Biology
000008401 1001_ $$0P:(DE-HGF)0$$aArakawa, M.$$b0
000008401 245__ $$aThe importance of valine 114 in ligand binding in beta(2)-adrenergic receptor
000008401 260__ $$aHoboken, NJ$$bWiley$$c2010
000008401 300__ $$a85 - 93
000008401 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000008401 440_0 $$010881$$aProtein Science$$v19$$x0961-8368$$y1
000008401 500__ $$aGrant sponsor: Manitoba Medical Service Foundation (MMSF); Grant sponsor: Canadian Institute of Health Research; Grant number: ROP 92389; Grant sponsor: Manitoba Health Research Council (MHRC); Grant sponsor: National Institutes of Health; Grant number: NIH-NLM 2RO1LM007994-05; Grant sponsor: National Science Foundation; Grant number: CAREER NSF-CC0449117; Grant sponsor: New Investigator Personnel Award from the Heart and Stroke Foundation of Canada (HSFC).
000008401 520__ $$aG-protein coupled receptors (GPCRs) are transmembrane signaling molecules, with a majority of them performing important physiological roles. beta(2)-Adrenergic receptor (beta(2)-AR) is a well-studied GPCRs that mediates natural responses to the hormones adrenaline and noradrenaline. Analysis of the ligand-binding region of beta(2)-AR using the recently solved high-resolution crystal structures revealed a number of highly conserved amino acids that might be involved in ligand binding. However, detailed structure-function studies on some of these residues have not been performed, and their role in ligand binding remains to be elucidated. In this study, we have investigated the structural and functional role of a highly conserved residue valine 114, in hamster beta(2)-AR by site-directed mutagenesis. We replaced V114 in hamster beta(2)-AR with a number of amino acid residues carrying different functional groups. In addition to the complementary substitutions V114I and V114L, the V114C and V114E mutants also showed significant ligand binding and agonist dependent G-protein activation. However, the V114G, V114T, V114S, and V114W mutants failed to bind ligand in a specific manner. Molecular modeling studies were conducted to interpret these results in structural terms. We propose that the replacement of V114 influences not only the interaction of the ethanolamine side-chains but also the aryl-ring of the ligands tested. Results from this study show that the size and orientation of the hydrophobic residue at position V114 in beta(2)-AR affect binding of both agonists and antagonists, but it does not influence the receptor expression or folding.
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000008401 65320 $$2Author$$abeta(2)-adrenergic receptor
000008401 65320 $$2Author$$avaline 114
000008401 65320 $$2Author$$aligand binding
000008401 65320 $$2Author$$asite-directed mutagenesis
000008401 65320 $$2Author$$amolecular modeling
000008401 650_2 $$2MeSH$$aAdenylate Cyclase: metabolism
000008401 650_2 $$2MeSH$$aAdrenergic beta-Antagonists: pharmacology
000008401 650_2 $$2MeSH$$aAlprenolol: pharmacology
000008401 650_2 $$2MeSH$$aAnimals
000008401 650_2 $$2MeSH$$aBinding Sites
000008401 650_2 $$2MeSH$$aCOS Cells
000008401 650_2 $$2MeSH$$aCercopithecus aethiops
000008401 650_2 $$2MeSH$$aCricetinae
000008401 650_2 $$2MeSH$$aCyclic AMP: metabolism
000008401 650_2 $$2MeSH$$aModels, Molecular
000008401 650_2 $$2MeSH$$aMutagenesis, Site-Directed
000008401 650_2 $$2MeSH$$aProtein Binding: drug effects
000008401 650_2 $$2MeSH$$aReceptors, Adrenergic, beta-2: chemistry
000008401 650_2 $$2MeSH$$aReceptors, Adrenergic, beta-2: genetics
000008401 650_2 $$2MeSH$$aReceptors, Adrenergic, beta-2: metabolism
000008401 650_2 $$2MeSH$$aValine: chemistry
000008401 650_2 $$2MeSH$$aValine: metabolism
000008401 650_7 $$00$$2NLM Chemicals$$aAdrenergic beta-Antagonists
000008401 650_7 $$00$$2NLM Chemicals$$aReceptors, Adrenergic, beta-2
000008401 650_7 $$013655-52-2$$2NLM Chemicals$$aAlprenolol
000008401 650_7 $$060-92-4$$2NLM Chemicals$$aCyclic AMP
000008401 650_7 $$07004-03-7$$2NLM Chemicals$$aValine
000008401 650_7 $$0EC 4.6.1.1$$2NLM Chemicals$$aAdenylate Cyclase
000008401 650_7 $$2WoSType$$aJ
000008401 7001_ $$0P:(DE-HGF)0$$aYanamala, N.$$b1
000008401 7001_ $$0P:(DE-HGF)0$$aUpadhyaya, J.$$b2
000008401 7001_ $$0P:(DE-HGF)0$$aHalayako, A.$$b3
000008401 7001_ $$0P:(DE-Juel1)VDB44599$$aKlein-Seetharaman, J.$$b4$$uFZJ
000008401 7001_ $$0P:(DE-HGF)0$$aChelikani, P.$$b5
000008401 773__ $$0PERI:(DE-600)2000025-X$$a10.1002/pro.285$$gp. 85 - 93$$p85 - 93$$q85 - 93$$tProtein science$$x0961-8368$$y2010
000008401 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817842
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000008401 9201_ $$0I:(DE-Juel1)ISB-2-20090406$$d31.12.2010$$gISB$$kISB-2$$lMolekulare Biophysik$$x0
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