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PDBsum entry 3eqf
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References listed in PDB file
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Key reference
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Title
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Crystal structures of mek1 binary and ternary complexes with nucleotides and inhibitors.
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Authors
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T.O.Fischmann,
C.K.Smith,
T.W.Mayhood,
J.E.Myers,
P.Reichert,
A.Mannarino,
D.Carr,
H.Zhu,
J.Wong,
R.S.Yang,
H.V.Le,
V.S.Madison.
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Ref.
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Biochemistry, 2009,
48,
2661-2674.
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PubMed id
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Abstract
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MEK1 is a member of the MAPK signal transduction pathway that responds to growth
factors and cytokines. We have determined that the kinase domain spans residues
35-382 by proteolytic cleavage. The complete kinase domain has been crystallized
and its X-ray crystal structure as a complex with magnesium and ATP-gammaS
determined at 2.1 A. Unlike crystals of a truncated kinase domain previously
published, the crystals of the intact domain can be grown either as a binary
complex with a nucleotide or as a ternary complex with a nucleotide and one of a
multitude of allosteric inhibitors. Further, the crystals allow for the
determination of costructures with ATP competitive inhibitors. We describe the
structures of nonphosphorylated MEK1 (npMEK1) binary complexes with ADP and
K252a, an ATP-competitive inhibitor (see Table 1), at 1.9 and 2.7 A resolution,
respectively. Ternary complexes have also been solved between npMEK1, a
nucleotide, and an allosteric non-ATP competitive inhibitor: ATP-gammaS with
compound 1 and ADP with either U0126 or the MEK1 clinical candidate PD325089 at
1.8, 2.0, and 2.5 A, respectively. Compound 1 is structurally similar to
PD325901. These structures illustrate fundamental differences among various
mechanisms of inhibition at the molecular level. Residues 44-51 have previously
been shown to play a negative regulatory role in MEK1 activity. The crystal
structure of the integral kinase domain provides a structural rationale for the
role of these residues. They form helix A and repress enzymatic activity by
stabilizing an inactive conformation in which helix C is displaced from its
active state position. Finally, the structure provides for the first time a
molecular rationale that explains how mutations in MEK may lead to the
cardio-facio-cutaneous syndrome.
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