The matrix metallo proteinases (MMPs) are strongly implicated in abnormal tissue degradation. Specific pathologic roles of the MMPs type IV collagenase and stromelysin are to facilitate tumor metastasis and invasion by degradation of the cellular basement membranes.Stromelysin is also involved in the destruction of tissue associated with arthritic diseases. These factors generate a strong interest to understand the three-dimensional structure and function of the MMPs in detail and to develop specific inhibitors of these proteins. Recent developments in nuclear magnetic resonance (NMR) make solution structure determinations for proteins up to 25 kDa feasible. It is proposed to use these new techniques to determine the solution structure of the 20 kDa catalytic domain of stromelysin, complexed with an inhibitor. The interaction between a peptide representing the prosequence of the stromelysin and the catalytic domain will also be investigated by NMR. Extensive homologies of the stromelysin domain with similar regions in other members of MMP family suggest that the structure determination of this domain will help understand the functioning of the metallo proteinase family as a whole. The knowledge of the three-dimensional structure of the catalytic site of these enzymes should aid in the development of potential inhibitors against the MMPs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052406-05
Application #
2750007
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1994-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Organized Research Units
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Van Doren, S R; Kurochkin, A V; Hu, W et al. (1995) Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor. Protein Sci 4:2487-98