Award details

Analysis of the mechanism of TIMP-MMP interactions and strategies for the development of `designer' TIMPs

Reference	C10217
Principal Investigator / Supervisor	Professor Gillian Murphy
Co-Investigators / Co-Supervisors	Dr Richard Williamson
Institution	University of East Anglia
Department	Biological Sciences
Funding type	Research
Value (£)	179,668
Status	Completed
Type	Research Grant
Start date	01/10/1998
End date	31/03/2002
Duration	42 months

Abstract

The proposed research expands our previous work on the mechanism of inhibition of matrix metalloproteinases (MMPs) by their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Using real time kinetic analyses we plan to extend and exploit new knowledge of the solution and crystal structures of MMP-TIMP complexes in order to determine the features of TIMPs that are responsible for the initial rapid binding to MMPs and the inhibition of enzyme activity. The elucidation of the TIMP binding mechanism will contribute significantly to our understanding of molecular recognition in protein-protein interactions. Specific TIMP mutants will be prepared in order to compare the role of individual residues in the binding of MMP2, MMP13 and MMP14, in comparison to other MMPs. The data will be used to identify modifications of the N and C-subdomains of TIMP2 that will abrogate its role in the cell surface activation of MMPs which are key activities in promoting tumour development. The design of such TIMP variants is an important prerequisite for their use in gene therapy approaches to the directed control of MMP activity.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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