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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},
}