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

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    21 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)4413-4421
    Number of pages9
    JournalJournal of Medicinal Chemistry
    Volume56
    Issue number11
    DOIs
    Publication statusPublished - 13 Jun 2013

    Keywords

    • MEK5-ERK5 PATHWAY
    • BREAST-CANCER
    • PROSTATE-CANCER
    • GROWTH-FACTOR
    • TARGETED DELETION
    • ACTIVATED PROTEIN-KINASE
    • IDENTIFICATION
    • BMK1/ERK5
    • EXPRESSION
    • SIGNALING PATHWAY

    Cite this

    Elkins, J. M., Wang, J., Deng, X., Pattison, M. J., Arthur, J. S. C., Erazo, T., Gomez, N., Lizcano, J. M., Gray, N. S., & Knapp, S. (2013). X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor. Journal of Medicinal Chemistry, 56(11), 4413-4421. https://doi.org/10.1021/jm4000837