title: 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.
authors: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
authors: Jonathan M
authors: JM
authors: Elkins
authors: Jing
authors: J
authors: Wang
authors: Xianming
authors: X
authors: Deng
authors: Michael J
authors: MJ
authors: Pattison
authors: J Simon C
authors: JS
authors: Arthur
authors: Tatiana
authors: T
authors: Erazo
authors: Nestor
authors: N
authors: Gomez
authors: Jose M
authors: JM
authors: Lizcano
authors: Nathanael S
authors: NS
authors: Gray
authors: Stefan
authors: S
authors: Knapp
mesh_terms: D000595:Amino Acid Sequence; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
chemical_list: D001381:Azepines; D011743:Pyrimidines; D048054:Mitogen-Activated Protein Kinase 7
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