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Hydrolase/hydrolase inhibitor PDB id
1bqq
Jmol
Contents
Protein chains
174 a.a. *
184 a.a. *
Metals
_CA ×2
_ZN ×2
Waters ×311
* Residue conservation analysis
PDB id:
1bqq
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the mt1-mmp--timp-2 complex
Structure: Membrane-type matrix metalloproteinase. Chain: m. Synonym: cdmt1-mmp. Matrix metalloproteinase-14. Mmp-14. Mt-mmp 1. Mtmmp1. Engineered: yes. Metalloproteinase inhibitor 2. Chain: t. Synonym: timp-2. Tissue inhibitor of metalloproteinases-2. Collagenase inhibitor.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Bos taurus. Cattle. Organism_taxid: 9913. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.75Å     R-factor:   0.189     R-free:   0.248
Authors: C.Fernandez-Catalan,W.Bode,R.Huber,D.Turk,J.J.Calvete, A.Lichte,H.Tschesche,K.Maskos
Key ref:
C.Fernandez-Catalan et al. (1998). Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. EMBO J, 17, 5238-5248. PubMed id: 9724659 DOI: 10.1093/emboj/17.17.5238
Date:
18-Aug-98     Release date:   18-Aug-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P50281  (MMP14_HUMAN) -  Matrix metalloproteinase-14
Seq:
Struc: 		 
Seq:
Struc: 		582 a.a.
174 a.a.
Protein chain
Pfam   ArchSchema ?
P16368  (TIMP2_BOVIN) -  Metalloproteinase inhibitor 2
Seq:
Struc: 		220 a.a.
184 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain M: E.C.3.4.24.80  - Membrane-type matrix metalloproteinase-1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   5 terms 
  Biological process     negative regulation of cell proliferation   5 terms 
  Biochemical function     enzyme inhibitor activity     9 terms  

 

 
DOI no: 10.1093/emboj/17.17.5238 EMBO J 17:5238-5248 (1998)
PubMed id: 9724659  
 
 
Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor.
C.Fernandez-Catalan, W.Bode, R.Huber, D.Turk, J.J.Calvete, A.Lichte, H.Tschesche, K.Maskos.
 
  ABSTRACT  
 
The proteolytic activity of matrix metalloproteinases (MMPs) towards extracellular matrix components is held in check by the tissue inhibitors of metalloproteinases (TIMPs). The binary complex of TIMP-2 and membrane-type-1 MMP (MT1-MMP) forms a cell surface located 'receptor' involved in pro-MMP-2 activation. We have solved the 2.75 A crystal structure of the complex between the catalytic domain of human MT1-MMP (cdMT1-MMP) and bovine TIMP-2. In comparison with our previously determined MMP-3-TIMP-1 complex, both proteins are considerably tilted to one another and show new features. CdMT1-MMP, apart from exhibiting the classical MMP fold, displays two large insertions remote from the active-site cleft that might be important for interaction with macromolecular substrates. The TIMP-2 polypeptide chain, as in TIMP-1, folds into a continuous wedge; the A-B edge loop is much more elongated and tilted, however, wrapping around the S-loop and the beta-sheet rim of the MT1-MMP. In addition, both C-terminal edge loops make more interactions with the target enzyme. The C-terminal acidic tail of TIMP-2 is disordered but might adopt a defined structure upon binding to pro-MMP-2; the Ser2 side-chain of TIMP-2 extends into the voluminous S1' specificity pocket of cdMT1-MMP, with its Ogamma pointing towards the carboxylate of the catalytic Glu240. The lower affinity of TIMP-1 for MT1-MMP compared with TIMP-2 might be explained by a reduced number of favourable interactions.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 Front view ribbon of the MMP -TIMP complexes. Figures drawn with SETOR (Evans, 1993). (A) Complex formed between cdMT1-MMP (top, gold) and TIMP-2 (bottom, orange). The N-terminus of MT1-MMP extends to the left, and the C-terminus of TIMP-2 to the bottom. Strands and helices are labelled, the six disulfide bridges of TIMP-2 are displayed in green, and the spheres represent the catalytic and structural zinc (central and upper pink sphere), and calcium 1 and 2 (right and left white sphere) of cdMT1-MMP. (B) Superposition of the complex formed between cdMT1-MMP (gold) and TIMP-2 (orange) with the complex (Gomis-Rüth et al., 1997) formed between cdMMP-3 (blue) and TIMP-1 (grey). Both MMP components superimpose well, while the two TIMP components are twisted to one another. 		Figure 2.
Figure 2 Binding of the interacting edge segments of TIMP-2 (stick models with carbons in yellow, nitrogens in blue, oxygens in red, and sulphurs in green, labels in white) and the zinc (pink spheres) to the substrate binding region of MT1-MMP (green model, black labels), which is viewed through the half-transparent enzyme surface (blue). The catalytic (ZN001) and the structural zinc (ZN002), and one of both calcium ions (KA003) are shown as pink and red spheres, respectively. For the sake of simplicity, not all contacting segments are shown. This (standard orientation) view is achieved after an 90° rotation of the complex in Figure 1 around a horizontal axis, so that now the active-site cleft runs across the MMP surface. Figures made by a combination of GRASP (Nicholls et al., 1993) and MOLSCRIPT (Kraulis, 1991). (A) Interaction of the sA -sB loop (represented by residues IleI35 to IleI43, left), the sC -connector loop (residues AlaI68 to CysI72, centre) and the N-terminal segment (CysI1 to ProI5, right) with the 'left side' part of the active-site cleft. (B) Interaction of the N-terminal segment (CysI1 to ProI5), the sG -sH loop (ArgI132 to IleI136) and the multiple turn loop (TrpI151, ThrI153 to IleI157) with the 'right side' part of the active-site cleft.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1998, 17, 5238-5248) copyright 1998.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21295090 L.Zhu, H.Wang, L.Wang, Y.Wang, K.Jiang, C.Li, Q.Ma, S.Gao, L.Wang, W.Li, M.Cai, H.Wang, G.Niu, S.Lee, W.Yang, X.Fang, and X.Chen (2011).
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PDB code: 2j0t
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Processing, shedding, and endocytosis of membrane type 1-matrix metalloproteinase (MT1-MMP).
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Distinct roles of catalytic and pexin-like domains in membrane-type matrix metalloproteinase (MMP)-mediated pro-MMP-2 activation and collagenolysis.
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Drosophila TIMP is a potent inhibitor of MMPs and TACE: similarities in structure and function to TIMP-3.
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Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
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  Proc Natl Acad Sci U S A, 99, 7414-7419.
PDB code: 1gxd
12374789 H.S.Kai, G.S.Butler, C.J.Morrison, A.E.King, G.R.Pelman, and C.M.Overall (2002).
Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain.
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Disulfide bond assignments of secreted Frizzled-related protein-1 provide insights about Frizzled homology and netrin modules.
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Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.
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Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme.
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11959855 S.J.Kridel, H.Sawai, B.I.Ratnikov, E.I.Chen, W.Li, A.Godzik, A.Y.Strongin, and J.W.Smith (2002).
A unique substrate binding mode discriminates membrane type-1 matrix metalloproteinase from other matrix metalloproteinases.
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11501766 B.Stratmann, M.Farr, and H.Tschesche (2001).
Characterization of C-terminally truncated human tissue inhibitor of metalloproteinases-4 expressed in Pichia pastoris.
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11584019 C.J.Morrison, G.S.Butler, H.F.Bigg, C.R.Roberts, P.D.Soloway, and C.M.Overall (2001).
Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway.
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Characterization of the role of the "MT-loop": an eight-amino acid insertion specific to progelatinase A (MMP2) activating membrane-type matrix metalloproteinases.
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Recognition and catabolism of synthetic heterotrimeric collagen peptides by matrix metalloproteinases.
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Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation.
  J Biol Chem, 275, 12080-12089.  
10827175 Z.Wang, R.Juttermann, and P.D.Soloway (2000).
TIMP-2 is required for efficient activation of proMMP-2 in vivo.
  J Biol Chem, 275, 26411-26415.  
9933646 C.M.Overall, A.E.King, D.K.Sam, A.D.Ong, T.T.Lau, U.M.Wallon, Y.A.DeClerck, and J.Atherstone (1999).
Identification of the tissue inhibitor of metalloproteinases-2 (TIMP-2) binding site on the hemopexin carboxyl domain of human gelatinase A by site-directed mutagenesis. The hierarchical role in binding TIMP-2 of the unique cationic clusters of hemopexin modules III and IV.
  J Biol Chem, 274, 4421-4429.  
10419448 H.Nagase, and J.F.Woessner (1999).
Matrix metalloproteinases.
  J Biol Chem, 274, 21491-21494.  
10415723 L.Blavier, P.Henriet, S.Imren, and Y.A.Declerck (1999).
Tissue inhibitors of matrix metalloproteinases in cancer.
  Ann N Y Acad Sci, 878, 108-119.  
10415762 M.Hutton, G.S.Butler, B.A.Wattam, F.Willenbrock, R.A.Williamson, and G.Murphy (1999).
Analysis of the interaction of TIMP-2 and MMPs: engineering the changes.
  Ann N Y Acad Sci, 878, 524-527.  
10409697 P.T.Wingfield, J.K.Sax, S.J.Stahl, J.Kaufman, I.Palmer, V.Chung, M.L.Corcoran, D.E.Kleiner, and W.G.Stetler-Stevenson (1999).
Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions.
  J Biol Chem, 274, 21362-21368.  
10187802 Q.Meng, V.Malinovskii, W.Huang, Y.Hu, L.Chung, H.Nagase, W.Bode, K.Maskos, and K.Brew (1999).
Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1' residue of substrate.
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The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.