Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell.

ABSTRACT: Developing selective inhibitors for proteolytic enzymes that share high sequence homology and structural similarity is important for achieving high target affinity and functional specificity. Here, we used a combination of yeast surface display and dual-color selective library screening to obtain selective inhibitors for each of the matrix metalloproteinases (MMPs) MMP14 and MMP9 by modifying the non-specific N-terminal domain of the tissue inhibitor of metalloproteinase-2 (N-TIMP2). We generated inhibitor variants with 30- to 1175-fold improved specificity to each of the proteases, respectively, relative to wild type N-TIMP2. These biochemical results accurately predicted the selectivity and specificity obtained in cell-based assays. In U87MG cells, the activation of MMP2 by MMP14 was inh

SUBMITTER: Arkadash V 

PROVIDER: S-EPMC6112833 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature