title: Mechanistic investigations of matrix metalloproteinase-8 inhibition by metal abstraction peptide.
abstract: The mechanism of matrix metalloproteinase-8 (MMP-8) inhibition was investigated using ellipsometric measurements of the interaction of MMP-8 with a surface bound peptide inhibitor, tether-metal abstraction peptide (MAP), bound to self-assembled monolayer films. MMP-8 is a collagenase whose activity and dysregulation have been implicated in a number of disease states, including cancer metastasis, diabetic neuropathy, and degradation of biomedical reconstructions, including dental restorations. Regulation of activity of MMP-8 and other matrix metalloproteinases is thus a significant, but challenging, therapeutic target. Strong inhibition of MMP-8 activity has recently been achieved via the small metal binding peptide tether-MAP. Here, the authors elucidate the mechanism of this inhibition and demonstrate that it occurs through the direct interaction of the MAP Tag and the Zn(2+) binding site in the MMP-8 active site. This enhanced understanding of the mechanism of inhibition will allow the design of more potent inhibitors as well as assays important for monitoring critical MMP levels in disease states.
authors.affiliation: Bioengineering Research Center, University of Kansas, Lawrence, Kansas 66045 and Department of Chemistry, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Jenifer K
authors.initials: JK
authors.lastname: Tucker
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.
authors.forename: Michaela L
authors.initials: ML
authors.lastname: McNiff
authors.affiliation: Bioengineering Research Center, University of Kansas, Lawrence, Kansas 66045 and Department of Chemistry, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Sasanka B
authors.initials: SB
authors.lastname: Ulapane
authors.affiliation: Bioengineering Research Center, University of Kansas, Lawrence, Kansas 66045 and Department of Mechanical Engineering, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Paulette
authors.initials: P
authors.lastname: Spencer
authors.affiliation: Bioengineering Research Center, University of Kansas, Lawrence, Kansas 66045 and Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Laurence
authors.affiliation: Bioengineering Research Center, University of Kansas, Lawrence, Kansas 66045 and Department of Chemistry, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Berrie
mesh_terms: D020134:Catalytic Domain; D003067:Coenzymes / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism*; D011485:Protein Binding; D015032:Zinc / Q000378:metabolism
chemical_list: D003067:Coenzymes; D010455:Peptides; D011480:Protease Inhibitors; D020784:Matrix Metalloproteinase 8; D015032:Zinc