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Hydrolase/hydrolase inhibitor PDB id
1cgl
Jmol
Contents
Protein chains
168 a.a. *
157 a.a. *
Ligands
0ED ×2
Metals
_ZN ×4
_CA ×2
Waters ×195
* Residue conservation analysis
PDB id:
1cgl
Name: Hydrolase/hydrolase inhibitor
Title: Structure of the catalytic domain of fibroblast collagenase with an inhibitor
Structure: Fibroblast collagenase. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21(de3). Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
Resolution:
2.40Å     R-factor:   0.186    
Authors: B.Lovejoy,A.Cleasby,A.M.Hassell,K.Longley,M.A.Luther,D.Weigl G.Mcgeehan,A.B.Mcelroy,D.Drewry,M.H.Lambert,S.R.Jordan
Key ref: B.Lovejoy et al. (1994). Structure of the catalytic domain of fibroblast collagenase complexed with an inhibitor. Science, 263, 375-377. PubMed id: 8278810 DOI: 10.1126/science.8278810
Date:
17-Nov-93     Release date:   27-Feb-95    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03956  (MMP1_HUMAN) -  Interstitial collagenase
Seq:
Struc: 		469 a.a.
168 a.a.*
Protein chain
Pfam   ArchSchema ?
P03956  (MMP1_HUMAN) -  Interstitial collagenase
Seq:
Struc: 		469 a.a.
157 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.3.4.24.7  - Interstitial collagenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleaves preferentially one bond in native collagen. Cleavage of the triple helix of collagen at about three-quarters of the length of the molecule from the N-terminus, at 775-Gly-|-Ile-776 in the alpha-1(I) chain. Cleaves synthetic substrates and alpha-macroglobulins at bonds where P1' is a hydrophobic residue.
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular matrix   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     metallopeptidase activity     3 terms  

 

 
DOI no: 10.1126/science.8278810 Science 263:375-377 (1994)
PubMed id: 8278810  
 
 
Structure of the catalytic domain of fibroblast collagenase complexed with an inhibitor.
B.Lovejoy, A.Cleasby, A.M.Hassell, K.Longley, M.A.Luther, D.Weigl, G.McGeehan, A.B.McElroy, D.Drewry, M.H.Lambert.
 
  ABSTRACT  
 
Collagenase is a zinc-dependent endoproteinase and is a member of the matrix metalloproteinase (MMP) family of enzymes. The MMPs participate in connective tissue remodeling events and aberrant regulation has been associated with several pathologies. The 2.4 angstrom resolution structure of the inhibited enzyme revealed that, in addition to the catalytic zinc, there is a second zinc ion and a calcium ion which play a major role in stabilizing the tertiary structure of collagenase. Despite scant sequence homology, collagenase shares structural homology with two other endoproteinases, bacterial thermolysin and crayfish astacin. The detailed description of protein-inhibitor interactions present in the structure will aid in the design of compounds that selectively inhibit individual members of the MMP family. Such inhibitors will be useful in examining the function of MMPs in pathological processes.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17541420 J.Hu, P.E.Van den Steen, Q.X.Sang, and G.Opdenakker (2007).
Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases.
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17594190 P.K.Srivastava, S.G.Dastidar, and A.Ray (2007).
Chronic obstructive pulmonary disease: role of matrix metalloproteases and future challenges of drug therapy.
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14991672 T.Oost, C.Sukonpan, M.Brewer, M.Goodnough, W.Tepp, E.A.Johnson, and D.H.Rich (2003).
Design and synthesis of substrate-based inhibitors of botulinum neurotoxin type B metalloprotease.
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12656997 V.J.Uitto, C.M.Overall, and C.McCulloch (2003).
Proteolytic host cell enzymes in gingival crevice fluid.
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12887053 W.Bode, and K.Maskos (2003).
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
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11994741 C.E.Brinckerhoff, and L.M.Matrisian (2002).
Matrix metalloproteinases: a tail of a frog that became a prince.
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12032297 E.Morgunova, A.Tuuttila, U.Bergmann, and K.Tryggvason (2002).
Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.
  Proc Natl Acad Sci U S A, 99, 7414-7419.
PDB code: 1gxd
11592410 F.Grams, H.Brandstetter, S.D'Alò, D.Geppert, H.W.Krell, H.Leinert, V.Livi, E.Menta, A.Oliva, G.Zimmermann, F.Gram, H.Brandstetter, S.D'Alò, D.Geppert, H.W.Krell, H.Leinert, E.Livi VMenta, A.Oliva, and G.Zimmermann (2001).
Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors.
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11148046 J.E.Jackman, C.R.Raetz, and C.A.Fierke (2001).
Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site.
  Biochemistry, 40, 514-523.  
11164719 R.Giavazzi, and G.Taraboletti (2001).
Preclinical development of metalloproteasis inhibitors in cancer therapy.
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11605653 T.Fujisawa, S.Katakura, S.Odake, Y.Morita, J.Yasuda, I.Yasumatsu, and T.Morikawa (2001).
Design and synthesis of carboxylate inhibitors for matrix metalloproteinases.
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11223512 T.Hori, T.Kumasaka, M.Yamamoto, N.Nonaka, N.Tanaka, Y.Hashimoto, U.Ueki, and K.Takio (2001).
Structure of a new 'aspzincin' metalloendopeptidase from Grifola frondosa: implications for the catalytic mechanism and substrate specificity based on several different crystal forms.
  Acta Crystallogr D Biol Crystallogr, 57, 361-368.
PDB codes: 1g12 1ge5 1ge6 1ge7
11248710 V.Knäuper, M.L.Patterson, F.X.Gomis-Rüth, B.Smith, A.Lyons, A.J.Docherty, and G.Murphy (2001).
The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivity.
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  10673425 C.C.Deivanayagam, R.L.Rich, M.Carson, R.T.Owens, S.Danthuluri, T.Bice, M.Höök, and S.V.Narayana (2000).
Novel fold and assembly of the repetitive B region of the Staphylococcus aureus collagen-binding surface protein.
  Structure, 8, 67-78.
PDB codes: 1d2o 1d2p
  10662694 J.Ottl, D.Gabriel, G.Murphy, V.Knäuper, Y.Tominaga, H.Nagase, M.Kröger, H.Tschesche, W.Bode, and L.Moroder (2000).
Recognition and catabolism of synthetic heterotrimeric collagen peptides by matrix metalloproteinases.
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  10422833 A.G.Pavlovsky, M.G.Williams, Q.Z.Ye, D.F.Ortwine, C.F.Purchase, A.D.White, V.Dhanaraj, B.D.Roth, L.L.Johnson, D.Hupe, C.Humblet, and T.L.Blundell (1999).
X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity.
  Protein Sci, 8, 1455-1462.
PDB codes: 1b8y 1caq 1ciz 1qia 1qic
9888808 C.M.Holman, C.C.Kan, M.R.Gehring, and H.E.Van Wart (1999).
Role of His-224 in the anomalous pH dependence of human stromelysin-1.
  Biochemistry, 38, 677-681.  
10026247 D.E.Brodersen, J.Nyborg, and M.Kjeldgaard (1999).
Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free states.
  Biochemistry, 38, 1695-1704.
PDB codes: 2psr 3psr
10353819 F.J.Moy, P.K.Chanda, J.M.Chen, S.Cosmi, W.Edris, J.S.Skotnicki, J.Wilhelm, and R.Powers (1999).
NMR solution structure of the catalytic fragment of human fibroblast collagenase complexed with a sulfonamide derivative of a hydroxamic acid compound.
  Biochemistry, 38, 7085-7096.
PDB codes: 3ayk 4ayk
10522712 F.M.Martin, R.P.Beckett, C.L.Bellamy, P.F.Courtney, S.J.Davies, A.H.Drummond, R.Dodd, L.M.Pratt, S.R.Patel, M.L.Ricketts, R.S.Todd, A.R.Tuffnell, J.W.Ward, and M.Whittaker (1999).
The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
  Bioorg Med Chem Lett, 9, 2887-2892.  
10366106 G.N.Smith, E.A.Mickler, K.A.Hasty, and K.D.Brandt (1999).
Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme.
  Arthritis Rheum, 42, 1140-1146.  
10026271 J.E.Jackman, C.R.Raetz, and C.A.Fierke (1999).
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase of Escherichia coli is a zinc metalloenzyme.
  Biochemistry, 38, 1902-1911.  
10415743 J.F.Woessner (1999).
Matrix metalloproteinase inhibition. From the Jurassic to the third millennium.
  Ann N Y Acad Sci, 878, 388-403.  
10092871 J.Saarinen, H.G.Welgus, C.A.Flizar, N.Kalkkinen, and J.Helin (1999).
N-glycan structures of matrix metalloproteinase-1 derived from human fibroblasts and from HT-1080 fibrosarcoma cells.
  Eur J Biochem, 259, 829-840.  
  10545322 K.Briknarová, A.Grishaev, L.Bányai, H.Tordai, L.Patthy, and M.Llinás (1999).
The second type II module from human matrix metalloproteinase 2: structure, function and dynamics.
  Structure, 7, 1235-1245.
PDB code: 1cxw
  10226042 K.E.Hightower, and C.A.Fierke (1999).
Zinc-catalyzed sulfur alkyation:insights from protein farnesyltransferase.
  Curr Opin Chem Biol, 3, 176-181.  
10415721 W.Bode, C.Fernandez-Catalan, F.Grams, F.X.Gomis-Rüth, H.Nagase, H.Tschesche, and K.Maskos (1999).
Insights into MMP-TIMP interactions.
  Ann N Y Acad Sci, 878, 73-91.  
  9792098 B.C.Finzel, E.T.Baldwin, G.L.Bryant, G.F.Hess, J.W.Wilks, C.M.Trepod, J.E.Mott, V.P.Marshall, G.L.Petzold, R.A.Poorman, T.J.O'Sullivan, H.J.Schostarez, and M.A.Mitchell (1998).
Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.
  Protein Sci, 7, 2118-2126.
PDB codes: 1usn 2usn
  9827994 B.J.Stockman, D.J.Waldon, J.A.Gates, T.A.Scahill, D.A.Kloosterman, S.A.Mizsak, E.J.Jacobsen, K.L.Belonga, M.A.Mitchell, B.Mao, J.D.Petke, L.Goodman, E.A.Powers, S.R.Ledbetter, P.S.Kaytes, G.Vogeli, V.P.Marshall, G.L.Petzold, and R.A.Poorman (1998).
Solution structures of stromelysin complexed to thiadiazole inhibitors.
  Protein Sci, 7, 2281-2286.
PDB code: 3usn
9484219 F.J.Moy, P.K.Chanda, S.Cosmi, M.R.Pisano, C.Urbano, J.Wilhelm, and R.Powers (1998).
High-resolution solution structure of the inhibitor-free catalytic fragment of human fibroblast collagenase determined by multidimensional NMR.
  Biochemistry, 37, 1495-1504.
PDB codes: 1ayk 2ayk
9771478 G.I.Murray, M.E.Duncan, P.O'Neil, J.A.McKay, W.T.Melvin, and J.E.Fothergill (1998).
Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer.
  J Pathol, 185, 256-261.  
  9655333 H.Brandstetter, R.A.Engh, E.G.Von Roedern, L.Moroder, R.Huber, W.Bode, and F.Grams (1998).
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
  Protein Sci, 7, 1303-1309.
PDB codes: 1a85 1a86
9437511 R.A.Greenwald, L.M.Golub, N.S.Ramamurthy, M.Chowdhury, S.A.Moak, and T.Sorsa (1998).
In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation.
  Bone, 22, 33-38.  
  9590702 T.Kuga, K.Esato, N.Zempo, K.Fujioka, and K.Nakamura (1998).
Detection of type III collagen fragments in specimens of abdominal aortic aneurysms.
  Surg Today, 28, 385-390.  
9760240 Y.C.Li, X.Zhang, R.Melton, V.Ganu, and N.C.Gonnella (1998).
Solution structure of the catalytic domain of human stromelysin-1 complexed to a potent, nonpeptidic inhibitor.
  Biochemistry, 37, 14048-14056.
PDB code: 1bm6
9724722 Y.H.Ding, K.Javaherian, K.M.Lo, R.Chopra, T.Boehm, J.Lanciotti, B.A.Harris, Y.Li, R.Shapiro, E.Hohenester, R.Timpl, J.Folkman, and D.C.Wiley (1998).
Zinc-dependent dimers observed in crystals of human endostatin.
  Proc Natl Acad Sci U S A, 95, 10443-10448.
PDB code: 1bnl
  9461346 J.C.Müller, E.G.von Roedern, F.Grams, H.Nagase, and L.Moroder (1997).
Non-peptidic cysteine derivatives as inhibitors of matrix metalloproteinases.
  Biol Chem, 378, 1475-1480.  
9154920 J.J.Perona, C.A.Tsu, C.S.Craik, and R.J.Fletterick (1997).
Crystal structure of an ecotin-collagenase complex suggests a model for recognition and cleavage of the collagen triple helix.
  Biochemistry, 36, 5381-5392.
PDB code: 1azz
9063449 R.Vallon, R.Müller, D.Moosmayer, E.Gerlach, and P.Angel (1997).
The catalytic domain of activated collagenase I (MMP-1) is absolutely required for interaction with its specific inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1).
  Eur J Biochem, 244, 81-88.  
9063899 T.Fujii, Y.Hata, M.Oozeki, H.Moriyama, T.Wakagi, N.Tanaka, and T.Oshima (1997).
The crystal structure of zinc-containing ferredoxin from the thermoacidophilic archaeon Sulfolobus sp. strain 7.
  Biochemistry, 36, 1505-1513.  
8756473 A.R.Welch, C.M.Holman, M.Huber, M.C.Brenner, M.F.Browner, and H.E.Van Wart (1996).
Understanding the P1' specificity of the matrix metalloproteinases: effect of S1' pocket mutations in matrilysin and stromelysin-1.
  Biochemistry, 35, 10103-10109.  
  8970152 B.Podbilewicz (1996).
ADM-1, a protein with metalloprotease- and disintegrin-like domains, is expressed in syncytial organs, sperm, and sheath cells of sensory organs in Caenorhabditis elegans.
  Mol Biol Cell, 7, 1877-1893.  
  8729000 C.L.Wilson, and L.M.Matrisian (1996).
Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions.
  Int J Biochem Cell Biol, 28, 123-136.  
8639603 D.R.Wetmore, and K.D.Hardman (1996).
Roles of the propeptide and metal ions in the folding and stability of the catalytic domain of stromelysin (matrix metalloproteinase 3).
  Biochemistry, 35, 6549-6558.  
8961947 J.Cha, M.V.Pedersen, and D.S.Auld (1996).
Metal and pH dependence of heptapeptide catalysis by human matrilysin.
  Biochemistry, 35, 15831-15838.  
  8898355 M.A.Stolow, D.D.Bauzon, J.Li, T.Sedgwick, V.C.Liang, Q.A.Sang, and Y.B.Shi (1996).
Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development.
  Mol Biol Cell, 7, 1471-1483.  
8804571 Q.A.Sang, M.K.Bodden, and L.J.Windsor (1996).
Activation of human progelatinase A by collagenase and matrilysin: activation of procollagenase by matrilysin.
  J Protein Chem, 15, 243-253.  
8917445 R.A.Williamson, D.Natalia, C.K.Gee, G.Murphy, M.D.Carr, and R.B.Freedman (1996).
Chemically and conformationally authentic active domain of human tissue inhibitor of metalloproteinases-2 refolded from bacterial inclusion bodies.
  Eur J Biochem, 241, 476-483.  
8654408 S.Morante, L.Furenlid, G.Schiavo, F.Tonello, R.Zwilling, and C.Montecucco (1996).
X-ray absorption spectroscopy study of zinc coordination in tetanus neurotoxin, astacin, alkaline protease and thermolysin.
  Eur J Biochem, 235, 606-612.  
8888065 T.E.Cawston (1996).
Metalloproteinase inhibitors and the prevention of connective tissue breakdown.
  Pharmacol Ther, 70, 163-182.  
8836097 T.Fujii, Y.Hata, T.Wakagi, N.Tanaka, and T.Oshima (1996).
Novel zinc-binding centre in thermoacidophilic archaeal ferredoxins.
  Nat Struct Biol, 3, 834-837.
PDB code: 1xer
  8740360 V.Dhanaraj, Q.Z.Ye, L.L.Johnson, D.J.Hupe, D.F.Ortwine, J.B.Dunbar, J.R.Rubin, A.Pavlovsky, C.Humblet, and T.L.Blundell (1996).
X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily.
  Structure, 4, 375-386.  
8771234 C.Montecucco, and G.Schiavo (1995).
Structure and function of tetanus and botulinum neurotoxins.
  Q Rev Biophys, 28, 423-472.  
  16696000 D.J.Buttle, H.Bramwell, and A.P.Hollander (1995).
Proteolytic mechanisms of cartilage breakdown: a target for arthritis therapy?
  Clin Mol Pathol, 48, M167-M177.  
8561847 D.Soler, T.Nomizu, W.E.Brown, Y.Shibata, and D.S.Auld (1995).
Matrilysin: expression, purification, and characterization.
  J Protein Chem, 14, 511-520.  
7737183 F.Grams, P.Reinemer, J.C.Powers, T.Kleine, M.Pieper, H.Tschesche, R.Huber, and W.Bode (1995).
X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.
  Eur J Biochem, 228, 830-841.
PDB codes: 1jao 1jaq
7649159 H.Will, and B.Hinzmann (1995).
cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment.
  Eur J Biochem, 231, 602-608.  
  8535233 J.W.Becker, A.I.Marcy, L.L.Rokosz, M.G.Axel, J.J.Burbaum, P.M.Fitzgerald, P.M.Cameron, C.K.Esser, W.K.Hagmann, and J.D.Hermes (1995).
Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme.
  Protein Sci, 4, 1966-1976.
PDB codes: 1slm 1sln
7581298 O.Rossetto, F.Deloye, B.Poulain, R.Pellizzari, G.Schiavo, and C.Montecucco (1995).
The metallo-proteinase activity of tetanus and botulism neurotoxins.
  J Physiol Paris, 89, 43-50.  
  8527834 R.C.Jackson (1995).
Update on computer-aided drug design.
  Curr Opin Biotechnol, 6, 646-651.  
7588817 S.Harada, T.Kinoshita, N.Kasai, S.Tsunasawa, and F.Sakiyama (1995).
Complete amino acid sequence of a zinc metalloendoprotease from Streptomyces caespitosus.
  Eur J Biochem, 233, 683-686.  
  8580839 S.R.Van Doren, A.V.Kurochkin, W.Hu, Q.Z.Ye, L.L.Johnson, D.J.Hupe, and E.R.Zuiderweg (1995).
Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor.
  Protein Sci, 4, 2487-2498.
PDB codes: 1ums 1umt
8561849 T.Pourmotabbed, J.A.Aelion, D.Tyrrell, K.A.Hasty, C.H.Bu, and C.L.Mainardi (1995).
Role of the conserved histidine and aspartic acid residues in activity and stabilization of human gelatinase B: an example of matrix metalloproteinases.
  J Protein Chem, 14, 527-535.  
  7663339 W.Stöcker, F.Grams, U.Baumann, P.Reinemer, F.X.Gomis-Rüth, D.B.McKay, and W.Bode (1995).
The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases.
  Protein Sci, 4, 823-840.  
7583637 W.Stöcker, and W.Bode (1995).
Structural features of a superfamily of zinc-endopeptidases: the metzincins.
  Curr Opin Struct Biol, 5, 383-390.  
  8069228 E.E.Hodgkin, I.C.Gillman, and R.J.Gilbert (1994).
Retrospective analysis of a secondary structure prediction: the catalytic domain of matrix metalloproteinases.
  Protein Sci, 3, 984-986.  
7937731 L.Holm, and C.Sander (1994).
Searching protein structure databases has come of age.
  Proteins, 19, 165-173.  
7851740 S.K.Kochi, G.Schiavo, M.Mock, and C.Montecucco (1994).
Zinc content of the Bacillus anthracis lethal factor.
  FEMS Microbiol Lett, 124, 343-348.  
  7828434 S.S.Twining (1994).
Regulation of proteolytic activity in tissues.
  Crit Rev Biochem Mol Biol, 29, 315-383.  
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.