Elkins, Jonathan M.Wang, JingDeng, XianmingPattison, Michael J.Arthur, J. Simon C.Erazo, TatianaGomez, NestorLizcano, Jose M.Gray, NathanaelKnapp, Stefan2014-02-132013Elkins, Jonathan M., Jing Wang, Xianming Deng, Michael J. Pattison, J. Simon C. Arthur, Tatiana Erazo, Nestor Gomez, Jose M. Lizcano, Nathanael S. Gray, and Stefan Knapp. 2013. “X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor.” Journal of Medicinal Chemistry 56 (11): 4413-4421. doi:10.1021/jm4000837. http://dx.doi.org/10.1021/jm4000837.0022-2623http://nrs.harvard.edu/urn-3:HUL.InstRepos:11708540The 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.en-USArticleJournal Article2014-02-1310.1021/jm4000837