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

J Med Chem. 2013 Jun 13;56(11):4413-21. doi: 10.1021/jm4000837. Epub 2013 May 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Azepines / chemistry*
  • Azepines / pharmacology
  • Crystallography, X-Ray
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 7 / chemistry*
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Sequence Homology, Amino Acid


  • Azepines
  • Pyrimidines
  • Mitogen-Activated Protein Kinase 7