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

Jonathan M. Elkins, Jing Wang, Xianming Deng, Michael J. Pattison, J. Simon C. Arthur, Tatiana Erazo, Nestor Gomez, Jose M. Lizcano, Nathanael S. Gray, Stefan Knapp

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)


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. © 2013 American Chemical Society.
Original languageEnglish
Pages (from-to)4413-4421
JournalJournal of Medicinal Chemistry
Publication statusPublished - 13 Jun 2013


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