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PDBsum entry 1a85

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
1a85
Jmol
Contents
Protein chain
158 a.a. *
Ligands
0DY
Metals
_CA ×2
_ZN ×2
* Residue conservation analysis
PDB id:
1a85
Name: Hydrolase/hydrolase inhibitor
Title: Mmp8 with malonic and asparagine based inhibitor
Structure: Mmp-8. Chain: a. Synonym: matrix metalloproteinase-8. Ec: 3.4.24.34
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.00Å     R-factor:   not given    
Authors: H.Brandstetter,E.G.V.Roedern,F.Grams,R.A.Engh
Key ref:
H.Brandstetter et al. (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. PubMed id: 9655333 DOI: 10.1002/pro.5560070605
Date:
03-Apr-98     Release date:   27-Apr-99    
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: 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: 10.1002/pro.5560070605 Protein Sci 7:1303-1309 (1998)
PubMed id: 9655333  
 
 
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
H.Brandstetter, R.A.Engh, E.G.Von Roedern, L.Moroder, R.Huber, W.Bode, F.Grams.
 
  ABSTRACT  
 
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. The 2f0 - fc eletrondensity for inhibitor HONE-iBM-L-Asn-NHBn(m-NH2) atthezincbinding site. Thedensity confirms bindingofthe S-S stereoisomer. Disorder oftheisobutyl group isindicated by thebranchinofthedensityat Cp. ed spheres ndicae watermolecules:anetwork of waterisinvolved in binding.
Figure 4.
Fig. 4. Schematic summaryofbinding interactions for HONH-iBM-L-Asp-NHBn,and HONH-~BM-L-A~~-NHBN(~-NH~). CH-0 type are listedinparentheses.lthough the ovrallsetof interactions emain similar, specific interactions change with the eta-aino group of HONH-iBM-L-Asn-NHBn(m-NH2) (hydrogen bond to Leu193CO).theAsp-Asnrepacement (likely interposi- ionofawater molecule), anda shift n the inhibitor position (weaker interactions toawater molecule).
 
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1998, 7, 1303-1309) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
15616985 A.Láng, I.G.Csizmadia, and A.Perczel (2005).
Peptide models XLV: conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins.
  Proteins, 58, 571-588.  
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.  
10713532 I.Broutin-L'Hermite, M.Ries-Kautt, and A.Ducruix (2000).
1.7 A x-ray structure of space-grown collagenase crystals.
  Acta Crystallogr D Biol Crystallogr, 56, 376-378.  
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.