X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4413-4421
• 全文大小：527K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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鈥搈esenchymal 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.