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 journalArticle

    16 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., ... 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
    Elkins, Jonathan M. ; Wang, Jing ; Deng, Xianming ; Pattison, Michael J. ; Arthur, J. Simon C. ; Erazo, Tatiana ; Gomez, Nestor ; Lizcano, Jose M. ; Gray, Nathanael S. ; Knapp, Stefan. / X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 11. pp. 4413-4421.
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    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.",
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    Elkins, JM, Wang, J, Deng, X, Pattison, MJ, Arthur, JSC, Erazo, T, Gomez, N, Lizcano, JM, Gray, NS & Knapp, S 2013, 'X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor', Journal of Medicinal Chemistry, vol. 56, no. 11, pp. 4413-4421. https://doi.org/10.1021/jm4000837

    X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor. / Elkins, Jonathan M.; Wang, Jing; Deng, Xianming; Pattison, Michael J.; Arthur, J. Simon C.; Erazo, Tatiana; Gomez, Nestor; Lizcano, Jose M.; Gray, Nathanael S.; Knapp, Stefan.

    In: Journal of Medicinal Chemistry, Vol. 56, No. 11, 13.06.2013, p. 4413-4421.

    Research output: Contribution to journalArticle

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    AU - Elkins, Jonathan M.

    AU - Wang, Jing

    AU - Deng, Xianming

    AU - Pattison, Michael J.

    AU - Arthur, J. Simon C.

    AU - Erazo, Tatiana

    AU - Gomez, Nestor

    AU - Lizcano, Jose M.

    AU - Gray, Nathanael S.

    AU - Knapp, Stefan

    PY - 2013/6/13

    Y1 - 2013/6/13

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    AB - 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.

    KW - MEK5-ERK5 PATHWAY

    KW - BREAST-CANCER

    KW - PROSTATE-CANCER

    KW - GROWTH-FACTOR

    KW - TARGETED DELETION

    KW - ACTIVATED PROTEIN-KINASE

    KW - IDENTIFICATION

    KW - BMK1/ERK5

    KW - EXPRESSION

    KW - SIGNALING PATHWAY

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    DO - 10.1021/jm4000837

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    JF - Journal of Medicinal Chemistry

    SN - 0022-2623

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    ER -