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


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.

SUBMITTER: Elkins JM 

PROVIDER: S-EPMC3683888 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

Elkins Jonathan M JM   Wang Jing J   Deng Xianming X   Pattison Michael J MJ   Arthur J Simon C JS   Erazo Tatiana T   Gomez Nestor N   Lizcano Jose M JM   Gray Nathanael S NS   Knapp Stefan S  

Journal of medicinal chemistry 20130517 11


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(  ...[more]

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