5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner

Bioorg Med Chem Lett. 2015 Feb 1;25(3):593-6. doi: 10.1016/j.bmcl.2014.12.011. Epub 2014 Dec 13.

Abstract

5Z-7-Oxozeaenol (5Z7O) is a covalent bonding inhibitor against the several protein kinases (e.g., ERK2 and TAK1) that possess a free cysteine at the gatekeeper-2 position. In addition to this cysteine, MAP2K7 has three other cysteine residues that are candidate for covalent bonding by the inhibitor 5Z7O. The crystal structure of the MAP2K7/5Z7O complex revealed that the inhibitor binds to MAP2K7 at a cysteine residue located at the end of the hinge region and not at the gatekeeper-2 residue. The structural insights into the interaction of 5Z7O with MAP2K7 should aid the development of 5Z7O derivatives with improved potency and selectivity.

Keywords: Covalent bonding inhibitor; Crystal structure; Cysteine; MAP kinase kinase 7.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Cysteine / chemistry*
  • MAP Kinase Kinase 7 / chemistry*
  • MAP Kinase Kinase 7 / metabolism
  • Mitogen-Activated Protein Kinase 1 / chemistry
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Zearalenone / analogs & derivatives*
  • Zearalenone / chemistry

Substances

  • 7-oxozeanol
  • Zearalenone
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase 1
  • MAP Kinase Kinase 7
  • Cysteine