Abstract
Map kinases are drug targets for autoimmune disease, cancer, and apoptosis-related diseases. Drug discovery efforts have developed MAP kinase inhibitors directed toward the ATP binding site and neighboring "DFG-out" site, both of which are targets for inhibitors of other protein kinases. On the other hand, MAP kinases have unique substrate and small molecule binding sites that could serve as inhibition sites. The substrate and processing enzyme D-motif binding site is present in all MAP kinases, and has many features of a good small molecule binding site. Further, the MAP kinase p38alpha has a binding site near its C-terminus discovered in crystallographic studies. Finally, the MAP kinases ERK2 and p38alpha have a second substrate binding site, the FXFP binding site that is exposed in active ERK2 and the D-motif peptide induced conformation of MAP kinases. Crystallographic evidence of these latter two binding sites is presented.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Review
MeSH terms
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Amino Acid Motifs
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Animals
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Antineoplastic Agents / metabolism
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Binding Sites
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Crystallography, X-Ray
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Flavonoids / metabolism
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Humans
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Mitogen-Activated Protein Kinase 1 / chemistry
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinases / chemistry*
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Mitogen-Activated Protein Kinases / metabolism*
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Protein Binding
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Protein Conformation
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Protein Kinase Inhibitors / metabolism
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Sulindac / analogs & derivatives
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Sulindac / metabolism
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p38 Mitogen-Activated Protein Kinases / chemistry
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antineoplastic Agents
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Flavonoids
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Protein Kinase Inhibitors
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Sulindac
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sulindac sulfide
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one