3V96

Complex of matrix metalloproteinase-10 catalytic domain (MMP-10cd) with tissue inhibitor of metalloproteinases-1 (TIMP-1)

Summary for 3V96

• Entry DOI: 10.2210/pdb3v96/pdb
• Descriptor: Metalloproteinase inhibitor 1, Stromelysin-2, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: metzincin, ob-fold, metalloproteinase, protease inhibitor, hydrolase inhibitor-hydrolase complex, hydrolase inhibitor/hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01033; Secreted, extracellular space, extracellular matrix (Probable): P09238
• Total number of polymer chains: 2
• Total formula weight: 39701.38

Authors

Batra, J.,Soares, A.S.,Radisky, E.S. (deposition date: 2011-12-23, release date: 2012-03-28, Last modification date: 2024-11-27)

Primary citation

Batra, J.,Robinson, J.,Soares, A.S.,Fields, A.P.,Radisky, D.C.,Radisky, E.S.
Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure.
J.Biol.Chem., 287:15935-15946, 2012

PubMed 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 (K(i)) of putative physiological inhibitors TIMP-1 and TIMP-2 for the active catalytic domain of human MMP-10 (MMP-10cd) using multiple kinetic approaches. We find that TIMP-1 inhibits the MMP-10cd with a K(i) 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 K(i) of 5.8 × 10(-9) M, which is again 10-fold weaker than the inhibition of MMP-3cd by this inhibitor (K(i) = 5.5 × 10(-10) M). We solved the x-ray crystal structure of TIMP-1 bound to the MMP-10cd at 1.9 Å resolution; the structure was solved by molecular replacement and refined with an R-factor of 0.215 (R(free) = 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.

PubMed: 22427646
DOI: 10.1074/jbc.M112.341156

Experimental method

X-RAY DIFFRACTION (1.9 Å)