Butler, Georgina S. and Hutton, Mike and Wattam, Beth A. and Williamson, Richard A. and Knauper, Vera and Willenbrock, Frances and Murphy, Glynis H. (1999) The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. Journal of Biological Chemistry, 274 (29). pp. 20391-20396. 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)
|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. (Contact us about this Publication)|
Residues 1-127 of human TIMP-8 (N-TIMP-2), comprising three of the disulfide-bonded loops of the TIMP-8 molecule, is a discrete protein domain that folds independently of the C-terminal domain. This domain has been shown to be necessary and sufficient for metalloproteinase inhibition and contains the major sites of interaction with the catalytic N-terminal domain of active matrix metalloproteinases (MMPs), Residues identified as being involved in the interaction with MMPs by NMR chemical shift perturbation studies and TIMP/MMP crystal structures have been altered by site directed mutagenesis. We show, by measurement of association rates and apparent inhibition constants, that the specificity of these N-TIMP-2 mutants for a range of MMPs can be altered by single site mutations in either the TIMP "ridge" (Cys(1)-Cys(3) and Ser(68)-Cys(72)) Or the flexible AB loop (Ser(31)-Ile(41)). This work demonstrates that it is possible to engineer TIMPs with altered specificity and suggests that this form of protein engineering may be useful in the treatment of diseases such as arthritis and cancer where the selective inhibition of key MMPs is desirable.
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences|
|Depositing User:||M. Nasiriavanaki|
|Date Deposited:||02 Jul 2009 08:01|
|Last Modified:||29 May 2014 15:50|
|Resource URI:||https://kar.kent.ac.uk/id/eprint/17163 (The current URI for this page, for reference purposes)|