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PDBsum entry 1jao

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
1jao
Jmol
Contents
Protein chain
158 a.a. *
Ligands
0D3
Metals
_ZN ×2
_CA ×2
Waters ×285
* Residue conservation analysis
PDB id:
1jao
Name: Hydrolase/hydrolase inhibitor
Title: Complex of 3-mercapto-2-benzylpropanoyl-ala-gly-nh2 with the domain of matrix metallo proteinase-8 (met80 form)
Structure: Matrix metallo proteinase-8 (met80 form). Chain: a. Fragment: catalytic domain, residues 80 - 242. Synonym: mmp-8-met80 form. Engineered: yes. Other_details: mmp-8 is identical to the human neutrophil c
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: neutrophils. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.40Å     R-factor:   0.183    
Authors: F.Grams,P.Reinemer,J.C.Powers,T.Kleine,M.Piper,H.Tschesche,R W.Bode
Key ref: F.Grams et al. (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. PubMed id: 7737183
Date:
11-Mar-96     Release date:   11-Jul-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P22894  (MMP8_HUMAN) -  Neutrophil collagenase
Seq:
Struc:
467 a.a.
158 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.34  - Neutrophil collagenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage of interstitial collagens in the triple helical domain. Unlike EC 3.4.24.7, this enzyme cleaves type III collagen more slowly than type I.
      Cofactor: Calcium; 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  

 

 
Eur J Biochem 228:830-841 (1995)
PubMed id: 7737183  
 
 
X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.
F.Grams, P.Reinemer, J.C.Powers, T.Kleine, M.Pieper, H.Tschesche, R.Huber, W.Bode.
 
  ABSTRACT  
 
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases involved in tissue remodeling. They have also been implicated in various disease processes including tumour invasion and joint destruction and are therefore attractive targets for inhibitor design. For rational drug design, information of inhibitor binding at the atomic level is essential. Recently, we have published the refined high-resolution crystal structure of the catalytic domain of human neutrophil collagenase (HNC) complexed with the inhibitor Pro-Leu-Gly-NHOH, which is a mimic for the unprimed (P3-P1) residues of a bound peptide substrate. We have now determined two additional HNC complexes formed with the thiol inhibitor HSCH2CH(CH2Ph)CO-L-Ala-Gly-NH2 and another hydroxamate inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2, which were both refined to R-values of 0.183/0.198 at 0.240/0.225-nm resolution. The inhibitor thiol and hydroxamate groups ligand the catalytic zinc, giving rise to a slightly distorted tetrahedral and trigonal-bipyramidal coordination sphere, respectively. The thiol inhibitor diastereomer with S-configuration at the P1' residue (corresponding to an L-amino acid analog) binds to HNC. Its peptidyl moiety mimics binding of primed (P1'-P3') residues of the substrate. In combination with our first structure a continuous hexapeptide corresponding to a peptide substrate productively bound to HNC was constructed and energy-minimized. Proteolytic cleavage of this Michaelis complex is probably general base-catalyzed as proposed for thermolysin, i.e. a glutamate assists nucleophilic attack of a water molecule. Although there are many structural and mechanistic similarities to thermolysin, substrate binding to MMPs differs due to the interactions beyond S1'-P1'. While thermolysin binds substrates with a kink at P1', substrates are bound in an extended conformation in the collagenases. This property explains the tolerance of thermolysin for D-amino acid residues at the P1' position, in contrast to the collagenases. The third inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2, unexpectedly binds in a different manner than anticipated from its design and binding mode in thermolysin. Its hydroxamate group obviously interacts with the catalytic zinc in a favourable bidentate manner, but in contrast its isobutyl (iBu) side chain remains outside of the S1' pocket, presumably due to severe constraints imposed by the adjacent planar hydroxamate group. Instead, the C-terminal Ala-Gly-NH2 tail adopts a bent conformation and inserts into this S1' pocket, presumably in a non-optimized manner. Both the isobutyl side chain and the C-terminal peptide tail could be replaced by other, better fitting groups.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18362965 P.Geurink, T.Klein, M.Leeuwenburgh, G.van der Marel, H.Kauffman, R.Bischoff, and H.Overkleeft (2008).
A peptide hydroxamate library for enrichment of metalloproteinases: towards an affinity-based metalloproteinase profiling protocol.
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17607744 A.Khandelwal, and S.Balaz (2007).
QM/MM linear response method distinguishes ligand affinities for closely related metalloproteins.
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17299501 C.M.Overall, and C.P.Blobel (2007).
In search of partners: linking extracellular proteases to substrates.
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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.
  Nat Rev Drug Discov, 6, 480-498.  
16107143 A.Khandelwal, V.Lukacova, D.Comez, D.M.Kroll, S.Raha, and S.Balaz (2005).
A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands.
  J Med Chem, 48, 5437-5447.  
15611040 D.Jozic, G.Bourenkov, N.H.Lim, R.Visse, H.Nagase, W.Bode, and K.Maskos (2005).
X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding.
  J Biol Chem, 280, 9578-9585.
PDB code: 1su3
14718924 B.E.Turk, T.Y.Wong, R.Schwarzenbacher, E.T.Jarrell, S.H.Leppla, R.J.Collier, R.C.Liddington, and L.C.Cantley (2004).
The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.
  Nat Struct Mol Biol, 11, 60-66.
PDB codes: 1pwq 1pwu 1pwv 1pww
12591933 E.I.Chen, W.Li, A.Godzik, E.W.Howard, and J.W.Smith (2003).
A residue in the S2 subsite controls substrate selectivity of matrix metalloproteinase-2 and matrix metalloproteinase-9.
  J Biol Chem, 278, 17158-17163.  
14581186 G.C.Fadda, D.Lairez, B.Arrio, J.P.Carton, and V.Larreta-Garde (2003).
Enzyme-catalyzed gel proteolysis: an anomalous diffusion-controlled mechanism.
  Biophys J, 85, 2808-2817.  
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.  
11694539 E.I.Chen, S.J.Kridel, E.W.Howard, W.Li, A.Godzik, and J.W.Smith (2002).
A unique substrate recognition profile for matrix metalloproteinase-2.
  J Biol Chem, 277, 4485-4491.  
12228918 J.L.Lauer-Fields, D.Juska, and G.B.Fields (2002).
Matrix metalloproteinases and collagen catabolism.
  Biopolymers, 66, 19-32.  
12437092 J.L.Lauer-Fields, and G.B.Fields (2002).
Triple-helical peptide analysis of collagenolytic protease activity.
  Biol Chem, 383, 1095-1105.  
12071970 K.F.Huang, S.H.Chiou, T.P.Ko, and A.H.Wang (2002).
Determinants of the inhibition of a Taiwan habu venom metalloproteinase by its endogenous inhibitors revealed by X-ray crystallography and synthetic inhibitor analogues.
  Eur J Biochem, 269, 3047-3056.
PDB codes: 1kug 1kui 1kuk
11953425 M.Gioia, G.F.Fasciglione, S.Marini, S.D'Alessio, G.De Sanctis, O.Diekmann, M.Pieper, V.Politi, H.Tschesche, and M.Coletta (2002).
Modulation of the catalytic activity of neutrophil collagenase MMP-8 on bovine collagen I. Role of the activation cleavage and of the hemopexin-like domain.
  J Biol Chem, 277, 23123-23130.  
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.
  Biol Chem, 382, 1277-1285.  
11164719 R.Giavazzi, and G.Taraboletti (2001).
Preclinical development of metalloproteasis inhibitors in cancer therapy.
  Crit Rev Oncol Hematol, 37, 53-60.  
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.
  Eur J Biochem, 268, 1888-1896.  
10732980 A.Scozzafava, and C.T.Supuran (2000).
Protease inhibitors. Part 8: synthesis of potent Clostridium histolyticum collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties.
  Bioorg Med Chem, 8, 637-645.  
10785556 A.Scozzafava, and C.T.Supuran (2000).
Protease inhibitors - part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase.
  Eur J Med Chem, 35, 299-307.  
10913755 A.Scozzafava, M.A.Ilies, G.Manole, and C.T.Supuran (2000).
Protease inhibitors. Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties.
  Eur J Pharm Sci, 11, 69-79.  
11023917 G.F.Fasciglione, S.Marini, S.D'Alessio, V.Politi, and M.Coletta (2000).
pH- and temperature-dependence of functional modulation in metalloproteinases. A comparison between neutrophil collagenase and gelatinases A and B.
  Biophys J, 79, 2138-2149.  
10788434 J.L.Lauer-Fields, K.A.Tuzinski, K.Shimokawa, H.Nagase, and G.B.Fields (2000).
Hydrolysis of triple-helical collagen peptide models by matrix metalloproteinases.
  J Biol Chem, 275, 13282-13290.  
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.  
10415812 C.Gallina, E.Gavuzzo, C.Giordano, B.Gorini, F.Mazza, M.Paglialunga-Paradisi, G.Panini, G.Pochetti, and V.Politi (1999).
Phosphonate inhibitors of adamalysin II and matrix metalloproteinases.
  Ann N Y Acad Sci, 878, 700-702.  
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
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.  
10611646 J.D.Tyndall, and D.P.Fairlie (1999).
Conformational homogeneity in molecular recognition by proteolytic enzymes.
  J Mol Recognit, 12, 363-370.  
9920899 M.Roghani, J.D.Becherer, M.L.Moss, R.E.Atherton, H.Erdjument-Bromage, J.Arribas, R.K.Blackburn, G.Weskamp, P.Tempst, and C.P.Blobel (1999).
Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity.
  J Biol Chem, 274, 3531-3540.  
10194346 T.Meinnel, L.Patiny, S.Ragusa, and S.Blanquet (1999).
Design and synthesis of substrate analogue inhibitors of peptide deformylase.
  Biochemistry, 38, 4287-4295.  
9739094 E.Schlagenhauf, R.Etges, and P.Metcalf (1998).
The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63).
  Structure, 6, 1035-1046.
PDB code: 1lml
  9521103 F.X.Gomis-Rüth, E.F.Meyer, L.F.Kress, and V.Politi (1998).
Structures of adamalysin II with peptidic inhibitors. Implications for the design of tumor necrosis factor alpha convertase inhibitors.
  Protein Sci, 7, 283-292.
PDB codes: 2aig 3aig
  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
  10082367 I.L.Alberts, K.Nadassy, and S.J.Wodak (1998).
Analysis of zinc binding sites in protein crystal structures.
  Protein Sci, 7, 1700-1716.  
9520379 K.Maskos, C.Fernandez-Catalan, R.Huber, G.P.Bourenkov, H.Bartunik, G.A.Ellestad, P.Reddy, M.F.Wolfson, C.T.Rauch, B.J.Castner, R.Davis, H.R.Clarke, M.Petersen, J.N.Fitzner, D.P.Cerretti, C.J.March, R.J.Paxton, R.A.Black, and W.Bode (1998).
Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme.
  Proc Natl Acad Sci U S A, 95, 3408-3412.
PDB code: 1bkc
  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.  
9249047 M.Betz, P.Huxley, S.J.Davies, Y.Mushtaq, M.Pieper, H.Tschesche, W.Bode, and F.X.Gomis-Rüth (1997).
1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile.
  Eur J Biochem, 247, 356-363.
PDB code: 1kbc
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.  
8765610 H.Nagase, and G.B.Fields (1996).
Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides.
  Biopolymers, 40, 399-416.  
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.  
8799115 R.Huber, P.Hof, R.O.Duarte, J.J.Moura, I.Moura, M.Y.Liu, J.LeGall, R.Hille, M.Archer, and M.J.Romão (1996).
A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes.
  Proc Natl Acad Sci U S A, 93, 8846-8851.  
8888065 T.E.Cawston (1996).
Metalloproteinase inhibitors and the prevention of connective tissue breakdown.
  Pharmacol Ther, 70, 163-182.  
  9164646 W.D.Shingleton, D.J.Hodges, P.Brick, and T.E.Cawston (1996).
Collagenase: a key enzyme in collagen turnover.
  Biochem Cell Biol, 74, 759-775.  
  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.  
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.