Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1
- 11 August 2000
- journal article
- research article
- Published by Elsevier BV in Journal of Molecular Biology
- Vol. 301 (2), 513-524
- https://doi.org/10.1006/jmbi.2000.3988
Abstract
The full three-dimensional structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent, sulfonamide hydroxamic acid inhibitor (CGS 27023) has been determined by NMR spectroscopy. The results reveal a core domain for the protein consisting of three alpha-helices and five beta-sheet strands with an overall tertiary fold similar to the catalytic domains of other matrix metalloproteinase family members. The S1' pocket, which is the major site of hydrophobic binding interaction, was found to be a wide cleft spanning the length of the protein and presenting facile opportunity for inhibitor extension deep into the pocket. Comparison with the reported X-ray structure of collagenase-3 showed evidence of flexibility for the loop region flanking the S1' pocket in both NMR and X-ray data. This flexibility was corroborated by NMR dynamics studies. Inhibitor binding placed the methoxy phenyl ring in the S1' pocket with the remainder of the molecule primarily solvent-exposed. The binding mode for this inhibitor was found to be similar with respect to stromelysin-1 and collagenase-1; however, subtle comparative differences in the interactions between inhibitor and enzyme were observed for the three MMPs that were consistent with their respective binding potencies.Keywords
This publication has 43 references indexed in Scilit:
- Crystal structure of the stromelysin catalytic domain at 2.0 Å resolution: inhibitor-induced conformational changesJournal of Molecular Biology, 1999
- Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.JCI Insight, 1997
- X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamilyStructure, 1996
- Stromelysin‐1: Three‐dimensional structure of the inhibited catalytic domain and of the C‐truncated proenzymeProtein Science, 1995
- Crystal structures of matrilysin-inhibitor complexesBiochemistry, 1995
- [5] Theoretical and practical aspects of proteinase inhibition kineticsMethods in enzymology, 1995
- Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitorNature Structural & Molecular Biology, 1994
- [2] Measurement of homo- and heteronuclear J couplings from quantitative J correlationMethods in enzymology, 1994
- Matrix Metalloproteinases: A ReviewCritical Reviews in Oral Biology & Medicine, 1993
- Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopyChemical Physics Letters, 1980