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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 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 languageAmerican English
Pages (from-to)1122-1134
Number of pages13
JournalFEBS Letters
Volume592
Issue number7
DOIs
StatePublished - Apr 2018

Bibliographical note

Funding Information:
This work was in part supported by the stage A grant from Yissum of the Hebrew University and Israel Science Foundation grant 1873/15 to JMS. NP is supported by the European Research Council ‘Ideas program’ ERC-2013-StG (contract grant number: 336041). ESR acknowledges support from U.S. National Institutes of Health grants R01CA154387 and R21CA205471.

Publisher Copyright:
© 2018 Federation of European Biochemical Societies

Keywords

  • binding specificity
  • matrix metalloproteinase inhibitors
  • protein engineering
  • protein–protein interactions

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