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PDBsum entry 3as2

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protein ligands links
Hydrolase/hydrolase inhibitor PDB id
3as2
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Contents
Protein chain
570 a.a.
Ligands
POY ×3
Waters ×588
PDB id:
3as2
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure analysis of chitinase a from vibrio harvey novel inhibitors - w275g mutant complex structure with propentofylline
Structure: Chitinase a. Chain: a. Fragment: residues 22-597. Engineered: yes. Mutation: yes
Source: Vibrio harveyi. Organism_taxid: 669. Strain: lmg7890. Gene: chia. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.149     R-free:   0.193
Authors: S.Pantoom,I.R.Vetter,H.Prinz,W.Suginta
Key ref: S.Pantoom et al. (2011). Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms. J Biol Chem, 286, 24312-24323. PubMed id: 21531720
Date:
09-Dec-10     Release date:   20-Apr-11    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9AMP1  (Q9AMP1_VIBHA) -  Chitinase A
Seq:
Struc:
 
Seq:
Struc:
850 a.a.
570 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.2.1.14  - Chitinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of the 1,4-beta-linkages of N-acetyl-D-glucosamine polymers of chitin.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     carbohydrate metabolic process   2 terms 
  Biochemical function     hydrolase activity, hydrolyzing O-glycosyl compounds     2 terms  

 

 
J Biol Chem 286:24312-24323 (2011)
PubMed id: 21531720  
 
 
Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms.
S.Pantoom, I.R.Vetter, H.Prinz, W.Suginta.
 
  ABSTRACT  
 
Six novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies.
 

 

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