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PDBsum entry 1pme
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References listed in PDB file
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Key reference
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Title
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A single amino acid substitution makes erk2 susceptible to pyridinyl imidazole inhibitors of p38 map kinase.
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Authors
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T.Fox,
J.T.Coll,
X.Xie,
P.J.Ford,
U.A.Germann,
M.D.Porter,
S.Pazhanisamy,
M.A.Fleming,
V.Galullo,
M.S.Su,
K.P.Wilson.
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Ref.
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Protein Sci, 1998,
7,
2249-2255.
[DOI no: ]
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PubMed id
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Abstract
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Mitogen-activated protein (MAP) kinases are serine/threonine kinases that
mediate intracellular signal transduction pathways. Pyridinyl imidazole
compounds block pro-inflammatory cytokine production and are specific p38 kinase
inhibitors. ERK2 is related to p38 in sequence and structure, but is not
inhibited by pyridinyl imidazole inhibitors. Crystal structures of two pyridinyl
imidazoles complexed with p38 revealed these compounds bind in the ATP site.
Mutagenesis data suggested a single residue difference at threonine 106 between
p38 and other MAP kinases is sufficient to confer selectivity of pyridinyl
imidazoles. We have changed the equivalent residue in human ERK2, Q105, into
threonine and alanine, and substituted four additional ATP binding site
residues. The single residue change Q105A in ERK2 enhances the binding of
SB202190 at least 25,000-fold compared to wild-type ERK2. We report enzymatic
analyses of wild-type ERK2 and the mutant proteins, and the crystal structure of
a pyridinyl imidazole, SB203580, bound to an ERK2 pentamutant, I103L, Q105T,
D106H, E109G. T110A. These ATP binding site substitutions induce low nanomolar
sensitivity to pyridinyl imidazoles. Furthermore, we identified 5-iodotubercidin
as a potent ERK2 inhibitor, which may help reveal the role of ERK2 in cell
proliferation.
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Figure 1.
Fig. 1. A: Chemicalstructures of ERK2 and p38 inhibitors I)
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Figure 2.
Fig. 2. See figurecaption n faingpage.
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The above figures are
reprinted
by permission from the Protein Society:
Protein Sci
(1998,
7,
2249-2255)
copyright 1998.
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