Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: Binding studies and crystal structure

Jyotica Batra, Jessica Robinson, Alexei S. Soares, Alan P. Fields, Derek C. Radisky, Evette S. Radisky

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Matrix metalloproteinase 10 (MMP-10, stromelysin-2) is a secreted metalloproteinase with functions in skeletal development, wound healing, and vascular remodeling; its overexpression is also implicated in lung tumorigenesis and tumor progression. To understand the regulation of MMP-10 by tissue inhibitors of metalloproteinases (TIMPs), we have assessed equilibrium inhibition constants (Ki) of putative physiological inhibitors TIMP-1 and TIMP-2 for the active catalytic domain of human MMP-10 (MMP-10cd) using multiple kinetic approaches.Wefind that TIMP-1 inhibits the MMP-10cd with a Ki of 1.1 × 10-9 M; this interaction is 10-fold weaker than the inhibition of the similar MMP-3 (stromelysin-1) catalytic domain (MMP-3cd) by TIMP-1. TIMP-2 inhibits the MMP- 10cd with a Ki of 5.8 × 10-9 M, which is again 10-fold weaker than the inhibition of MMP-3cd by this inhibitor (Ki = 5.5 ×10-10 M).Wesolved the x-ray crystal structure of TIMP-1 bound to theMMP-10cdat 1.9Å resolution; the structure was solved by molecular replacement and refined with an R-factor of 0.215 (Rfree = 0.266). Comparing our structure of MMP-10cd·TIMP-1 with the previously solved structure of MMP-3cd·TIMP-1 (Protein Data Bank entry 1UEA), we see substantial differences at the binding interface that provide insight into the differential binding of stromelysin family members to TIMP-1. This structural information may ultimately assist in the design of more selective TIMP-based inhibitors tailored for specificity toward individual members of the stromelysin family, with potential therapeutic applications.

Original languageEnglish (US)
Pages (from-to)15935-15946
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number19
DOIs
StatePublished - May 4 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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