Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14

Jason Shirian, Valeria Arkadash, Itay Cohen, Tamila Sapir, Evette S Radisky, Niv Papo, Julia M. Shifman

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
JournalFEBS Letters
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Binding specificity
  • Matrix metalloproteinase inhibitors
  • Protein engineering
  • Protein-protein interactions

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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