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PDBsum entry 3vug
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Transferase/transferase inhibitor
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PDB id
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3vug
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References listed in PDB file
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Key reference
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Title
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Seven cysteine-Deficient mutants depict the interplay between thermal and chemical stabilities of individual cysteine residues in mitogen-Activated protein kinase c-Jun n-Terminal kinase 1.
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Authors
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T.Nakaniwa,
H.Fukada,
T.Inoue,
M.Gouda,
R.Nakai,
Y.Kirii,
M.Adachi,
T.Tamada,
S.Segawa,
R.Kuroki,
T.Tada,
T.Kinoshita.
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Ref.
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Biochemistry, 2012,
51,
8410-8421.
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PubMed id
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Abstract
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Intracellular proteins can have free cysteines that may contribute to their
structure, function, and stability; however, free cysteines can lead to chemical
instabilities in solution because of oxidation-driven aggregation. The MAP
kinase, c-Jun N-terminal kinase 1 (JNK1), possesses seven free cysteines and is
an important drug target for autoimmune diseases, cancers, and apoptosis-related
diseases. To characterize the role of cysteine residues in the structure,
function, and stability of JNK1, we prepared and evaluated wild-type JNK1 and
seven cysteine-deficient JNK1 proteins. The nonreduced sodium dodecyl
sulfate-polyacrylamide gel electrophoresis experiments showed that the chemical
stability of JNK1 increased as the number of cysteines decreased. The
contribution of each cysteine residue to biological function and thermal
stability was highly susceptible to the environment surrounding the particular
cysteine mutation. The mutations of solvent-exposed cysteine to serine did not
influence biological function and increased the thermal stability. The mutation
of the accessible cysteine involved in the hydrophobic pocket did not affect
biological function, although a moderate thermal destabilization was observed.
Cysteines in the loosely assembled hydrophobic environment moderately
contributed to thermal stability, and the mutations of these cysteines had a
negligible effect on enzyme activity. The other cysteines are involved in the
tightly filled hydrophobic core, and mutation of these residues was found to
correlate with thermal stability and enzyme activity. These findings about the
role of cysteine residues should allow us to obtain a stable JNK1 and thus
promote the discovery of potent JNK1 inhibitors.
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