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PDBsum entry 1i73

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
1i73
Jmol
Contents
Protein chain
163 a.a. *
Ligands
PRO-LEU-PAT
Metals
_ZN ×2
_CA ×2
Waters ×281
* Residue conservation analysis
PDB id:
1i73
Name: Hydrolase/hydrolase inhibitor
Title: Complex of pro-leu-l-trp phosphonate with the catalitic doma matrix metallo proteinase-8 (met80 form)
Structure: Neutrophil collagenase. Chain: a. Fragment: residues 80-242. Synonym: matrix metalloproteinase-8. Mmp-8. Engineered: yes. Three residue peptide inhibitor. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the three residue peptide inhibitor was chem synthesized
Resolution:
1.40Å     R-factor:   0.138     R-free:   0.194
Authors: E.Gavuzzo,G.Pochetti,F.Mazza,C.Gallina,B.Gorini,S.D'Alessio, H.Tschesche,P.A.Tucker
Key ref: E.Gavuzzo et al. (2000). Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design. J Med Chem, 43, 3377-3385. PubMed id: 10978185 DOI: 10.1021/jm9909589
Date:
07-Mar-01     Release date:   21-Mar-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P22894  (MMP8_HUMAN) -  Neutrophil collagenase
Seq:
Struc:
467 a.a.
163 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: 10.1021/jm9909589 J Med Chem 43:3377-3385 (2000)
PubMed id: 10978185  
 
 
Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design.
E.Gavuzzo, G.Pochetti, F.Mazza, C.Gallina, B.Gorini, S.D'Alessio, M.Pieper, H.Tschesche, P.A.Tucker.
 
  ABSTRACT  
 
Two crystal structures of human neutrophil collagenase (HNC, MMP-8), one complexed with a primed- and the other with an unprimed-side inhibitor, were determined using synchrotron radiation at 100 K. Both inhibitors contain non-hydroxamate zinc-binding functions. The Pro-Leu-L-Trp(P)(OH)(2) occupies the unprimed region of the active site, furnishes new structural information regarding interaction between the catalytic zinc ion and the phosphonate group, and is the only example of occupation of the S(1) subsite of MMP-8 by the bulky tryptophan side chain. The (R)-2-(biphenyl-4-ylsulfonyl)-1,2,3, 4-tetrahydroisochinolin-3-carboxylic acid, a conformationally constrained D-Tic derivative, accommodates its biphenyl substituent into the deep primary specificity S(1)' subsite, inducing a widening of the entrance to this pocket; this modification of the protein, mainly consisting in a shift of the segment centered at Pro217, is observed for the first time in MMP-8 complexes. Cation-aromatic interactions can stabilize the formation of both complexes, and the beneficial effect of aromatic substituents in proximity of the catalytic zinc ion is discussed. The phosphonate group bound to either a primed- or unprimed-side inhibitor maintains the same relative position with respect to the catalytic zinc ion, suggesting that this binding function can be exploited for the design of combined inhibitors assembled to interact with both primed and unprimed regions of the active cleft.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17672455 J.Lauer-Fields, K.Brew, J.K.Whitehead, S.Li, R.P.Hammer, and G.B.Fields (2007).
Triple-helical transition state analogues: a new class of selective matrix metalloproteinase inhibitors.
  J Am Chem Soc, 129, 10408-10417.  
16708363 G.Bianchini, A.Bocedi, P.Ascenzi, E.Gavuzzo, F.Mazza, and M.Aschi (2006).
Molecular dynamics simulation of Leishmania major surface metalloprotease GP63 (leishmanolysin).
  Proteins, 64, 385-390.  
16446446 J.K.Kim, I.S.Yang, H.J.Shin, K.J.Cho, E.K.Ryu, S.H.Kim, S.S.Park, and K.H.Kim (2006).
Insight into autoproteolytic activation from the structure of cephalosporin acylase: a protein with two proteolytic chemistries.
  Proc Natl Acad Sci U S A, 103, 1732-1737.
PDB codes: 2adv 2ae3 2ae4 2ae5
15272157 A.W.Schüttelkopf, and D.M.van Aalten (2004).
PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.
  Acta Crystallogr D Biol Crystallogr, 60, 1355-1363.  
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.