2e2d
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Flexibility and variability of TIMP binding: X-ray structure of the complex between collagenase-3/MMP-13 and TIMP-2
OverviewOverview
The excessive activity of matrix metalloproteinases (MMPs) contributes to, pathological processes such as arthritis, tumor growth and metastasis if, not balanced by the tissue inhibitors of metalloproteinases (TIMPs). In, arthritis, the destruction of fibrillar (type II) collagen is one of the, hallmarks, with MMP-1 (collagenase-1) and MMP-13 (collagenase-3) being, identified as key players in arthritic cartilage. MMP-13, furthermore, has, been found in highly metastatic tumors. We have solved the 2.0 A crystal, structure of the complex between the catalytic domain of human MMP-13, (cdMMP-13) and bovine TIMP-2. The overall structure resembles our, previously determined MT1-MMP/TIMP-2 complex, in that the wedge-shaped, TIMP-2 inserts with its edge into the entire MMP-13 active site cleft., However, the inhibitor is, according to a relative rotation of, approximately 20 degrees, oriented differently relative to the proteinase., Upon TIMP binding, the catalytic zinc, the zinc-ligating side chains, the, enclosing MMP loop and the S1' wall-forming segment move significantly and, in concert relative to the rest of the cognate MMP, and the active site, cleft constricts slightly, probably allowing a more favourable interaction, between the Cys1(TIMP) alpha-amino group of the inhibitor and the, catalytic zinc ion of the enzyme. Thus, this structure supports the view, that the central N-terminal TIMP segment essentially defines the relative, positioning of the TIMP, while the flanking edge loops determine the, relative orientation, depending on the individual target MMP.
About this StructureAbout this Structure
2E2D is a Protein complex structure of sequences from Bos taurus and Homo sapiens with ZN and CA as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Flexibility and variability of TIMP binding: X-ray structure of the complex between collagenase-3/MMP-13 and TIMP-2., Maskos K, Lang R, Tschesche H, Bode W, J Mol Biol. 2007 Mar 2;366(4):1222-31. Epub 2006 Dec 1. PMID:17196980
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