PDBsum entry 2e2d

Hydrolase/hydrolase inhibitor

PDB id: 2e2d

Contents

Protein chains

165 a.a. *

180 a.a. *

Metals

_CA ×2

_ZN ×2

Waters ×323

* Residue conservation analysis

PDB id:

2e2d

Name:

Hydrolase/hydrolase inhibitor

Title:

Flexibility and variability of timp binding: x-ray structure of the complex between collagenase-3/mmp-13 and timp-2

Structure:

Matrix metallopeptidase 13. Chain: a. Fragment: catalytic domain. Synonym: mmp-13. Collagenase-3. Engineered: yes. Metalloproteinase inhibitor 2. Chain: c. Synonym: timp-2. Tissue inhibitor of metalloproteinases 2. Collagenase inhibitor.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mmp13. Expressed in: escherichia coli. Expression_system_taxid: 562. Bos taurus. Cattle. Organism_taxid: 9913.

Resolution:

2.00Å R-factor: 0.201 R-free: 0.231

Authors:

K.Maskos,R.Lang,H.Tschesche,W.Bode

Key ref:

K.Maskos et al. (2007). 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. PubMed id: 17196980 DOI: 10.1016/j.jmb.2006.11.072

Date:

11-Nov-06 Release date: 13-Mar-07

Protein chain

P45452  (MMP13_HUMAN) -  Collagenase 3 from Homo sapiens

Seq: 471 a.a.

Struc: 165 a.a.

Protein chain

P16368  (TIMP2_BOVIN) -  Metalloproteinase inhibitor 2 from Bos taurus

Seq: 220 a.a.

Struc: 180 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.24.- - ?????

DOI no: 10.1016/j.jmb.2006.11.072

J Mol Biol 366:1222-1231 (2007)

PubMed id: 17196980

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

K.Maskos, R.Lang, H.Tschesche, W.Bode.

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.

Selected figure(s)

Figure 1.
Figure 1. Stereo views of the cdMMP-13/TIMP-2 complex (blue ribbon, catalytic domain; orange ribbon, TIMP-2), optimally overlaid with the formerly determined cdMMP-14/TIMP-2 complex (grey rope, catalytic domain; green rope, TIMP-2).^25 Helices, strands and selected loops of the cdMMP-13/TIMP2 complex are labelled. Due to their more similar conformation, essentially both catalytic domains are superimposed. The MMP-13 catalytic domain differs in that the N-terminal segment nestles against the proteinase surface, forming a surface-located salt-bridge, and by lacking the characteristic MT-loop. (a) Front view. (b) Side view. Figure 1. Stereo views of the cdMMP-13/TIMP-2 complex (blue ribbon, catalytic domain; orange ribbon, TIMP-2), optimally overlaid with the formerly determined cdMMP-14/TIMP-2 complex (grey rope, catalytic domain; green rope, TIMP-2).[3]^25 Helices, strands and selected loops of the cdMMP-13/TIMP2 complex are labelled. Due to their more similar conformation, essentially both catalytic domains are superimposed. The MMP-13 catalytic domain differs in that the N-terminal segment nestles against the proteinase surface, forming a surface-located salt-bridge, and by lacking the characteristic MT-loop. (a) Front view. (b) Side view.

Figure 2.
Figure 2. Optimal superimposition of the MMP-13/TIMP-2 complex with the MMP-14/TIMP-2 complex.^25 CdMMP-13 is shown in surface representation with some residues indicated by blue labels, and MMP-14 is omitted for clarity. The stereo views show the detailed interactions of some TIMP-2 edge loops (orange) of the MMP-13/TIMP-2 complex and compare them with the TIMP-2 loops in the MMP-14/TIMP-2 complex (green). (a) Front view towards the left-hand side surface of cdMMP-13. The distal parts of the sA-sB loops of both TIMP-2 molecules are shown as stick models. (b) Front view towards the right-hand side surface of cdMMP-13 showing the interactions of the C-terminal parts of TIMP-2 with MMP-13 (surface) in comparison with the equivalent TIMP-2 segments in the MMP-14/TIMP-2 complex. Figure 2. Optimal superimposition of the MMP-13/TIMP-2 complex with the MMP-14/TIMP-2 complex.[3]^25 CdMMP-13 is shown in surface representation with some residues indicated by blue labels, and MMP-14 is omitted for clarity. The stereo views show the detailed interactions of some TIMP-2 edge loops (orange) of the MMP-13/TIMP-2 complex and compare them with the TIMP-2 loops in the MMP-14/TIMP-2 complex (green). (a) Front view towards the left-hand side surface of cdMMP-13. The distal parts of the sA-sB loops of both TIMP-2 molecules are shown as stick models. (b) Front view towards the right-hand side surface of cdMMP-13 showing the interactions of the C-terminal parts of TIMP-2 with MMP-13 (surface) in comparison with the equivalent TIMP-2 segments in the MMP-14/TIMP-2 complex.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 366, 1222-1231) copyright 2007.

Figures were selected by the author.