@article {Shirian2018-ri,
	title = {Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14},
	journal = {FEBS Lett.},
	volume = {592},
	number = {7},
	year = {2018},
	month = {apr},
	pages = {1122{\textendash}1134},
	publisher = {Wiley},
	abstract = {MMP-14 and MMP-9 are two well-established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a nonspecific MMP inhibitor, N-TIMP2. The engineered purified N-TIMP2 variants showed enhanced specificity toward MMP-14 and MMP-9 relative to a panel of off-target MMPs. MMP-specific N-TIMP2 sequence signatures were obtained that could be understood from the structural perspective of MMP/N-TIMP2 interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities.},
	keywords = {binding specificity, Matrix Metalloproteinase Inhibitors, protein engineering, protein-protein interactions},
	author = {Shirian, Jason and Arkadash, Valeria and Cohen, Itay and Sapir, Tamila and Radisky, Evette S and Papo, Niv and Shifman, Julia M}
}
