PUBLICATION
Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity
- Authors
- Morell, M., Nguyen Duc, T., Willis, A.L., Syed, S., Lee, J., Deu, E., Deng, Y., Xiao, J., Turk, B.E., Jessen, J.R., Weiss, S.J., Bogyo, M.
- ID
- ZDB-PUB-210803-18
- Date
- 2013
- Source
- Journal of the American Chemical Society 135: 9139-48 (Journal)
- Registered Authors
- Jessen, Jason R.
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Cell Line
- Cysteine/analysis
- Cysteine/genetics
- Cysteine/metabolism
- Humans
- Matrix Metalloproteinase 1/analysis*
- Matrix Metalloproteinase 1/genetics
- Matrix Metalloproteinase 1/metabolism
- Matrix Metalloproteinase 12/analysis*
- Matrix Metalloproteinase 12/genetics
- Matrix Metalloproteinase 12/metabolism
- Mice
- Models, Molecular
- Molecular Probe Techniques*
- Molecular Sequence Data
- Optical Imaging
- Protein Engineering/methods*
- Sequence Alignment
- Zebrafish
- PubMed
- 23701445 Full text @ J. Am. Chem. Soc.
Citation
Morell, M., Nguyen Duc, T., Willis, A.L., Syed, S., Lee, J., Deu, E., Deng, Y., Xiao, J., Turk, B.E., Jessen, J.R., Weiss, S.J., Bogyo, M. (2013) Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity. Journal of the American Chemical Society. 135:9139-48.
Abstract
Matrix metalloproteinases (MMPs) are zinc endopeptidases that play roles in numerous pathophysiological processes and therefore are promising drug targets. However, the large size of this family and a lack of highly selective compounds that can be used for imaging or inhibition of specific MMPs members has limited efforts to better define their biological function. Here we describe a protein engineering strategy coupled with small-molecule probe design to selectively target individual members of the MMP family. Specifically, we introduce a cysteine residue near the active-site of a selected protease that does not alter its overall activity or function but allows direct covalent modification by a small-molecule probe containing a reactive electrophile. This specific engineered interaction between the probe and the target protease provides a means to both image and inhibit the modified protease with absolute specificity. Here we demonstrate the feasibility of the approach for two distinct MMP proteases, MMP-12 and MT1-MMP (or MMP-14).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping