2E2D

Flexibility and variability of TIMP binding: X-ray structure of the complex between collagenase-3/MMP-13 and TIMP-2

Summary for 2E2D

• Entry DOI: 10.2210/pdb2e2d/pdb
• Related: 1BQQ 1BR9 1BUV 830C
• Descriptor: Matrix metallopeptidase 13, Metalloproteinase inhibitor 2, ZINC ION, ... (5 entities in total)
• Functional Keywords: matrix metalloproteinase-mmp; collagenase; tissue inhibitor of metalloproteinases-timp; complex, flexibility, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P45452; Secreted: P16368
• Total number of polymer chains: 2
• Total formula weight: 39011.11

Authors

Maskos, K.,Lang, R.,Tschesche, H.,Bode, W. (deposition date: 2006-11-11, release date: 2007-03-13, Last modification date: 2024-11-06)

Primary citation

Maskos, K.,Lang, R.,Tschesche, H.,Bode, W.
Flexibility and Variability of TIMP Binding: X-ray Structure of the Complex Between Collagenase-3/MMP-13 and TIMP-2
J.Mol.Biol., 366:1222-1231, 2007

PubMed Abstract: 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.

PubMed: 17196980
DOI: 10.1016/j.jmb.2006.11.072

Experimental method

X-RAY DIFFRACTION (2 Å)