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The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.

Original publication

DOI

10.1021/jm4000837

Type

Journal article

Journal

J Med Chem

Publication Date

13/06/2013

Volume

56

Pages

4413 - 4421

Keywords

Amino Acid Sequence, Azepines, Crystallography, X-Ray, HEK293 Cells, HeLa Cells, Humans, Mitogen-Activated Protein Kinase 7, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Pyrimidines, Sequence Homology, Amino Acid