PDBsum entry 1hfs

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Hydrolase PDB id
Protein chain
160 a.a. *
_ZN ×2
_CA ×3
Waters ×143
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of the catalytic domain of human fibroblas stromelysin-1 inhibited with the n-carboxy-alkyl inhibitor
Structure: Stromelysin-1. Chain: a. Synonym: matrix metalloprotease-3, proteoglycanase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
1.70Å     R-factor:   0.189     R-free:   0.217
Authors: J.W.Becker
Key ref: C.K.Esser et al. (1997). Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides. J Med Chem, 40, 1026-1040. PubMed id: 9083493 DOI: 10.1021/jm960465t
13-Feb-97     Release date:   18-Feb-98    
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Protein chain
Pfam   ArchSchema ?
P08254  (MMP3_HUMAN) -  Stromelysin-1
477 a.a.
160 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Stromelysin 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
      Cofactor: Ca(2+); Zn(2+)
 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: 10.1021/jm960465t J Med Chem 40:1026-1040 (1997)
PubMed id: 9083493  
Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.
C.K.Esser, R.L.Bugianesi, C.G.Caldwell, K.T.Chapman, P.L.Durette, N.N.Girotra, I.E.Kopka, T.J.Lanza, D.A.Levorse, M.MacCoss, K.A.Owens, M.M.Ponpipom, J.P.Simeone, R.K.Harrison, L.Niedzwiecki, J.W.Becker, A.I.Marcy, M.G.Axel, A.J.Christen, J.McDonnell, V.L.Moore, J.M.Olszewski, C.Saphos, D.M.Visco, W.K.Hagmann.
Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

Literature references that cite this PDB file's key reference

  PubMed id Reference
17710450 L.A.Alcaraz, L.Banci, I.Bertini, F.Cantini, A.Donaire, and L.Gonnelli (2007).
Matrix metalloproteinase-inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors.
  J Biol Inorg Chem, 12, 1197-1206.
PDB codes: 2jnp 2jt5 2jt6
14732707 V.Lukacova, Y.Zhang, M.Mackov, P.Baricic, S.Raha, J.A.Calvo, and S.Balaz (2004).
Similarity of binding sites of human matrix metalloproteinases.
  J Biol Chem, 279, 14194-14200.  
12077439 P.A.Elkins, Y.S.Ho, W.W.Smith, C.A.Janson, K.J.D'Alessio, M.S.McQueney, M.D.Cummings, and A.M.Romanic (2002).
Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase.
  Acta Crystallogr D Biol Crystallogr, 58, 1182-1192.
PDB code: 1l6j
10644727 M.W.Olson, M.M.Bernardo, M.Pietila, D.C.Gervasi, M.Toth, L.P.Kotra, I.Massova, S.Mobashery, and R.Fridman (2000).
Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1.
  J Biol Chem, 275, 2661-2668.  
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
9446583 A.Mucha, P.Cuniasse, R.Kannan, F.Beau, A.Yiotakis, P.Basset, and V.Dive (1998).
Membrane type-1 matrix metalloprotease and stromelysin-3 cleave more efficiently synthetic substrates containing unusual amino acids in their P1' positions.
  J Biol Chem, 273, 2763-2768.  
  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
9704635 G.Keyszer, A.Redlich, T.Häupl, J.Zacher, M.Sparmann, U.Engethüm, S.Gay, and G.R.Burmester (1998).
Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry.
  Arthritis Rheum, 41, 1378-1387.  
9433876 J.S.Mudgett, N.I.Hutchinson, N.A.Chartrain, A.J.Forsyth, J.McDonnell, I.I.Singer, E.K.Bayne, J.Flanagan, D.Kawka, C.F.Shen, K.Stevens, H.Chen, M.Trumbauer, and D.M.Visco (1998).
Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction.
  Arthritis Rheum, 41, 110-121.  
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 codes are shown on the right.