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J Med Chem. 2013 Jun 13;56(11):4413-21. doi: 10.1021/jm4000837. Epub 2013 May 17.

X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor.

Author information

1
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.

Abstract

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.

PMID:
23656407
PMCID:
PMC3683888
DOI:
10.1021/jm4000837
[Indexed for MEDLINE]
Free PMC Article

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