High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3

Muskett, Frederick W. and Frenkiel, Tom A. and Feeney, James and Freedman, Robert B. and Carr, Mark D. and Williamson, Richard A. (1998) High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3. Journal of Biological Chemistry, 273 (34). pp. 21736-21743. ISSN 0021-9258. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1074/jbc.273.34.21736

Abstract

The high resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 (N-TIMP-2) in solution has been determined using multidimensional heteronuclear NMR spectroscopy, with the structural calculations based on an extensive set of constraints, including 3132 nuclear Overhauser effect-based distance constraints, 56 hydrogen bond constraints, and 220 torsion angle constraints (an average of 26.9 constraints/residue). The core of the protein consists of a five-stranded beta-barrel that is homologous to the beta-barrel found in the oligosaccharide/oligonucleotide binding protein fold. The binding site for the catalytic domain of matrix metalloproteinases-3 (N-MMP-3) on N-TIMP-2 has been mapped by determining the changes in chemical shifts on complex formation for signals from the protein backbone (15N, 13C, and 1H). This approach identified a discrete N-MMP-3 binding site on N-TIMP-2 composed of the N terminus of the protein and the loops between beta-strands AB, CD, and EF. The beta-hairpin formed from strands A and B in N-TIMP-2 is significantly longer than the equivalent structure in TIMP-1, allowing it to make more extensive binding interactions with the MMP catalytic domain. A detailed comparison of the N-TIMP-2 structure with that of TIMP-1 bound to N-MMP-3 (Gomis-Ruth, F.-X., Maskos, K., Betz, M., Bergner, A., Huber, R., Suzuki, K., Yoshida, N., Nagase, H., Brew, K., Bourne, G. P., Bartunik, H. & Bode, W. (1997) Nature 389, 77-80) revealed that the core beta-barrels are very similar in topology but that the loop connecting beta-strands CD (P67-C72) would need to undergo a large conformational change for TIMP-2 to bind in a similar manner to TIMP-1.

Item Type: Article
Additional information: 0021-9258 (Print) Journal Article Research Support, Non-U.S. Gov't
Uncontrolled keywords: Binding Sites Catalysis Hydrogen Bonding Magnetic Resonance Spectroscopy Matrix Metalloproteinase 3/*metabolism Models, Molecular Molecular Sequence Data Molecular Structure Protein Binding Protein Conformation Protein Folding Protein Structure, Secondary Tissue Inhibitor of Metalloproteinase-1/metabolism Tissue Inhibitor of Metalloproteinase-2/*metabolism
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Faculties > Science Technology and Medical Studies > School of Biosciences > Protein Science Group
Depositing User: Richard Williamson
Date Deposited: 24 Jun 2009 16:22
Last Modified: 16 Jun 2014 13:53
Resource URI: https://kar.kent.ac.uk/id/eprint/5313 (The current URI for this page, for reference purposes)
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