N-Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: Mode of binding in a complex with MMP-8

The first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of a matrix metalloproteinase is reported. The ligand and three other analogues were prepared and studied as inhibitors of MMP-2, MMP-3, and MMP-8. The crystal structure of the complex with MMP-8 shows that the N-hydroxyurea, contrary to the analogous hydroxamate, binds the catalytic zinc ion in a monodentate rather than bidentate mode and with high out-of-plane distortion of the amide bonds.

Graphical abstractThe first crystallographic structure of an N-hydroxyurea inhibitor bound into the active site of MMP-8 is reported. The hydroxyurea moiety, contrary to the analogous hydroxamate, binds the catalytic zinc ion as a monodentate rather than a bidentate ligand.Figure optionsDownload full-size imageDownload as PowerPoint slide