PDBsum entry 456c

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protein ligands metals Protein-protein interface(s) links
Matrix metalloprotease PDB id
Protein chains
160 a.a. *
CBP ×2
_ZN ×4
_CA ×2
Waters ×309
* Residue conservation analysis
PDB id:
Name: Matrix metalloprotease
Title: Crystal structure of collagenase-3 (mmp-13) complexed to a diphenyl-ether sulphone based hydroxamic acid
Structure: Mmp-13. Chain: a, b. Fragment: catalytic domain, residues 110-269. Synonym: collagenase-3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: cdna construct
2.40Å     R-factor:   0.216     R-free:   0.338
Authors: B.Lovejoy,A.Welch,S.Carr,C.Luong,C.Broka,R.T.Hendricks, J.Campbell,K.Walker,R.Martin,H.Van Wart,M.F.Browner
Key ref:
B.Lovejoy et al. (1999). Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nat Struct Biol, 6, 217-221. PubMed id: 10074939 DOI: 10.1038/6657
06-Aug-98     Release date:   06-Aug-99    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P45452  (MMP13_HUMAN) -  Collagenase 3
471 a.a.
160 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     collagen catabolic process   2 terms 
  Biochemical function     metallopeptidase activity     3 terms  


DOI no: 10.1038/6657 Nat Struct Biol 6:217-221 (1999)
PubMed id: 10074939  
Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors.
B.Lovejoy, A.R.Welch, S.Carr, C.Luong, C.Broka, R.T.Hendricks, J.A.Campbell, K.A.Walker, R.Martin, H.Van Wart, M.F.Browner.
The X-ray crystal structures of the catalytic domain of human collagenase-3 (MMP-13) and collagenase-1 (MMP-1) with bound inhibitors provides a basis for understanding the selectivity profile of a novel series of matrix metalloprotease (MMP) inhibitors. Differences in the relative size and shape of the MMP S1' pockets suggest that this pocket is a critical determinant of MMP inhibitor selectivity. The collagenase-3 S1' pocket is long and open, easily accommodating large P1' groups, such as diphenylether. In contrast, the collagenase-1 S1' pocket must undergo a conformational change to accommodate comparable P1' groups. The selectivity of the diphenylether series of inhibitors for collagenase-3 is largely determined by their affinity for the preformed S1' pocket of collagenase-3, as compared to the induced fit in collagenase-1.
  Selected figure(s)  
Figure 2.
Figure 2. The S1' pockets of collagenases-1 and -3. a, Collagense-3 with RS-130830 bound. b, Collagenase-1 with a peptide-based inhibitor (PDB^26, ^27 accession code 2TCL^15). c, Collagenase-1 in a complex with RS-104966. The S1' pockets are represented by a solid surface representation of the enzyme. The S1'-specificity loop is shown by a ribbon, and specificity residue is identified.
Figure 3.
Figure 3. The hydrogen bond interactions of inhibitors bound to collagenases-1 and -3. Collagenase-1 a, with a peptide-based inhibitor (2TCL) and b, with the diphenylether sulfone inhibitor, RS-104966 bound. Collagenase-3 with c, RS-130830 and d, RS-113456 bound.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 217-221) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference Google scholar

  PubMed id Reference
21370305 H.S.Shieh, A.G.Tomasselli, K.J.Mathis, M.E.Schnute, S.S.Woodard, N.Caspers, J.M.Williams, J.R.Kiefer, G.Munie, A.Wittwer, A.M.Malfait, and M.D.Tortorella (2011).
Structure analysis reveals the flexibility of the ADAMTS-5 active site.
  Protein Sci, 20, 735-744.
PDB codes: 3ljt 3ljz
  21520417 K.Edman, M.Furber, P.Hemsley, C.Johansson, G.Pairaudeau, J.Petersen, M.Stocks, A.Tervo, A.Ward, E.Wells, and L.Wissler (2011).
The discovery of MMP7 inhibitors exploiting a novel selectivity trigger.
  ChemMedChem, 6, 769-773.
PDB codes: 2y6c 2y6d
  19882751 J.D.Durrant, Oliveira, and J.A.McCammon (2010).
Including receptor flexibility and induced fit effects into the design of MMP-2 inhibitors.
  J Mol Recognit, 23, 173-182.  
19543729 O.D.I┼čeri, M.D.Kars, F.Arpaci, and U.Gündüz (2010).
Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins.
  Cancer Chemother Pharmacol, 65, 447-455.  
19287485 M.K.Kim, J.M.Shin, H.C.Eun, and J.H.Chung (2009).
The role of p300 histone acetyltransferase in UV-induced histone modifications and MMP-1 gene transcription.
  PLoS ONE, 4, e4864.  
19707688 M.Rouffet, C.Denhez, E.Bourguet, F.Bohr, and D.Guillaume (2009).
In silico study of MMP inhibition.
  Org Biomol Chem, 7, 3817-3825.  
17991750 H.S.Shieh, K.J.Mathis, J.M.Williams, R.L.Hills, J.F.Wiese, T.E.Benson, J.R.Kiefer, M.H.Marino, J.N.Carroll, J.W.Leone, A.M.Malfait, E.C.Arner, M.D.Tortorella, and A.Tomasselli (2008).
High resolution crystal structure of the catalytic domain of ADAMTS-5 (aggrecanase-2).
  J Biol Chem, 283, 1501-1507.
PDB code: 3b8z
17623656 A.R.Johnson, A.G.Pavlovsky, D.F.Ortwine, F.Prior, C.F.Man, D.A.Bornemeier, C.A.Banotai, W.T.Mueller, P.McConnell, C.Yan, V.Baragi, C.Lesch, W.H.Roark, M.Wilson, K.Datta, R.Guzman, H.K.Han, and R.D.Dyer (2007).
Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.
  J Biol Chem, 282, 27781-27791.
PDB codes: 2ow9 2ozr
17206645 A.Ravi, P.Garg, and S.V.Sitaraman (2007).
Matrix metalloproteinases in inflammatory bowel disease: boon or a bane?
  Inflamm Bowel Dis, 13, 97.  
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
  ChemMedChem, 2, 152-171.  
16710861 M.Matziari, V.Dive, and A.Yiotakis (2007).
Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors.
  Med Res Rev, 27, 528-552.  
17997411 R.Bhaskaran, M.O.Palmier, N.A.Bagegni, X.Liang, and S.R.Van Doren (2007).
Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment.
  J Mol Biol, 374, 1333-1344.
PDB code: 2poj
17460772 S.A.Tsareva, R.Moriggl, F.M.Corvinus, B.Wiederanders, A.Schütz, B.Kovacic, and K.Friedrich (2007).
Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction.
  Neoplasia, 9, 279-291.  
17065155 D.Minond, J.L.Lauer-Fields, M.Cudic, C.M.Overall, D.Pei, K.Brew, R.Visse, H.Nagase, and G.B.Fields (2006).
The roles of substrate thermal stability and P2 and P1' subsite identity on matrix metalloproteinase triple-helical peptidase activity and collagen specificity.
  J Biol Chem, 281, 38302-38313.  
16680577 J.F.Fisher, and S.Mobashery (2006).
Recent advances in MMP inhibitor design.
  Cancer Metastasis Rev, 25, 115-136.  
  17357475 Y.Zhao, W.Feng, Y.Yang, L.Ling, and R.Chen (2006).
Comparison of properties of tumor necrosis factor-alpha converting enzyme (TACE) and some matrix metalloproteases (MMPs) in catalytic domains.
  J Huazhong Univ Sci Technolog Med Sci, 26, 637-639.  
  15855654 G.A.Limb, K.Matter, G.Murphy, A.D.Cambrey, P.N.Bishop, G.E.Morris, and P.T.Khaw (2005).
Matrix metalloproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis.
  Am J Pathol, 166, 1555-1563.  
15533938 G.R.Pelman, C.J.Morrison, and C.M.Overall (2005).
Pivotal molecular determinants of peptidic and collagen triple helicase activities reside in the S3' subsite of matrix metalloproteinase 8 (MMP-8): the role of hydrogen bonding potential of ASN188 and TYR189 and the connecting cis bond.
  J Biol Chem, 280, 2370-2377.  
16356002 M.B.Onaran, A.B.Comeau, and C.T.Seto (2005).
Squaric acid-based peptidic inhibitors of matrix metalloprotease-1.
  J Org Chem, 70, 10792-10802.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12801404 R.P.Somerville, S.A.Oblander, and S.S.Apte (2003).
Matrix metalloproteinases: old dogs with new tricks.
  Genome Biol, 4, 216.  
12887053 W.Bode, and K.Maskos (2003).
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
  Biol Chem, 384, 863-872.  
11967260 E.Llano, G.Adam, A.M.Pendás, V.Quesada, L.M.Sánchez, I.Santamariá, S.Noselli, and C.López-Otín (2002).
Structural and enzymatic characterization of Drosophila Dm2-MMP, a membrane-bound matrix metalloproteinase with tissue-specific expression.
  J Biol Chem, 277, 23321-23329.  
11817584 J.A.Mengshol, K.S.Mix, and C.E.Brinckerhoff (2002).
Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull's-eye or missing the mark?
  Arthritis Rheum, 46, 13-20.  
10675720 A.M.Pendás, J.A.Uría, M.G.Jiménez, M.Balbín, J.P.Freije, and C.López-Otín (2000).
An overview of collagenase-3 expression in malignant tumors and analysis of its potential value as a target in antitumor therapies.
  Clin Chim Acta, 291, 137-155.  
10861846 C.R.Partridge, J.R.Hawker, and R.Forough (2000).
Overexpression of a secretory form of FGF-1 promotes MMP-1-mediated endothelial cell migration.
  J Cell Biochem, 78, 487-499.  
10809722 J.O.Stracke, M.Hutton, M.Stewart, A.M.Pendás, B.Smith, C.López-Otin, G.Murphy, and V.Knäuper (2000).
Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme.
  J Biol Chem, 275, 14809-14816.  
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.
  Chem Biol, 7, 119-132.  
11133099 T.E.Barta, D.P.Becker, L.J.Bedell, G.A.De Crescenzo, J.J.McDonald, G.E.Munie, S.Rao, H.S.Shieh, R.Stegeman, A.M.Stevens, and C.I.Villamil (2000).
Synthesis and activity of selective MMP inhibitors with an aryl backbone.
  Bioorg Med Chem Lett, 10, 2815-2817.  
11063573 X.Huang, F.Moy, and R.Powers (2000).
Evaluation of the utility of NMR structures determined from minimal NOE-based restraints for structure-based drug design, using MMP-1 as an example.
  Biochemistry, 39, 13365-13375.  
10455161 L.L.Johnson, D.A.Bornemeier, J.A.Janowicz, J.Chen, A.G.Pavlovsky, and D.F.Ortwine (1999).
Effect of species differences on stromelysin-1 (MMP-3) inhibitor potency. An explanation of inhibitor selectivity using homology modeling and chimeric proteins.
  J Biol Chem, 274, 24881-24887.  
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