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PDBsum entry 4ku7
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Signaling protein
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PDB id
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4ku7
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References listed in PDB file
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Key reference
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Title
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Structural basis for cyclic-Nucleotide selectivity and cgmp-Selective activation of pkg i.
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Authors
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G.Y.Huang,
J.J.Kim,
A.S.Reger,
R.Lorenz,
E.W.Moon,
C.Zhao,
D.E.Casteel,
D.Bertinetti,
B.Vanschouwen,
R.Selvaratnam,
J.W.Pflugrath,
B.Sankaran,
G.Melacini,
F.W.Herberg,
C.Kim.
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Ref.
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Structure, 2014,
22,
116-124.
[DOI no: ]
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PubMed id
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Abstract
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Cyclic guanosine monophosphate (cGMP) and cyclic AMP (cAMP)-dependent protein
kinases (PKG and PKA) are closely related homologs, and the cyclic nucleotide
specificity of each kinase is crucial for keeping the two signaling pathways
segregated, but the molecular mechanism of cyclic nucleotide selectivity is
unknown. Here, we report that the PKG Iβ C-terminal cyclic nucleotide binding
domain (CNB-B) is highly selective for cGMP binding, and we have solved crystal
structures of CNB-B with and without bound cGMP. These structures, combined with
a comprehensive mutagenic analysis, allowed us to identify Leu296 and Arg297 as
key residues that mediate cGMP selectivity. In addition, by comparing the cGMP
bound and unbound structures, we observed large conformational changes in the
C-terminal helices in response to cGMP binding, which were stabilized by
recruitment of Tyr351 as a "capping residue" for cGMP. The observed
rearrangements of the C-terminal helices provide a mechanical insight into
release of the catalytic domain and kinase activation.
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