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@ARTICLE{Arakawa:8401,
      author       = {Arakawa, M. and Yanamala, N. and Upadhyaya, J. and
                      Halayako, A. and Klein-Seetharaman, J. and Chelikani, P.},
      title        = {{T}he importance of valine 114 in ligand binding in
                      beta(2)-adrenergic receptor},
      journal      = {Protein science},
      volume       = {19},
      issn         = {0961-8368},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {PreJuSER-8401},
      pages        = {85 - 93},
      year         = {2010},
      note         = {Grant 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).},
      abstract     = {G-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.},
      keywords     = {Adenylate Cyclase: metabolism / Adrenergic
                      beta-Antagonists: pharmacology / Alprenolol: pharmacology /
                      Animals / Binding Sites / COS Cells / Cercopithecus aethiops
                      / Cricetinae / Cyclic AMP: metabolism / Models, Molecular /
                      Mutagenesis, Site-Directed / Protein Binding: drug effects /
                      Receptors, Adrenergic, beta-2: chemistry / Receptors,
                      Adrenergic, beta-2: genetics / Receptors, Adrenergic,
                      beta-2: metabolism / Valine: chemistry / Valine: metabolism
                      / Adrenergic beta-Antagonists (NLM Chemicals) / Receptors,
                      Adrenergic, beta-2 (NLM Chemicals) / Alprenolol (NLM
                      Chemicals) / Cyclic AMP (NLM Chemicals) / Valine (NLM
                      Chemicals) / Adenylate Cyclase (NLM Chemicals) / J
                      (WoSType)},
      cin          = {ISB-2},
      ddc          = {610},
      cid          = {I:(DE-Juel1)ISB-2-20090406},
      pnm          = {Programm Biosoft},
      pid          = {G:(DE-Juel1)FUEK443},
      shelfmark    = {Biochemistry $\&$ Molecular Biology},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:19916165},
      pmc          = {pmc:PMC2817842},
      UT           = {WOS:000273638700010},
      doi          = {10.1002/pro.285},
      url          = {https://juser.fz-juelich.de/record/8401},
}