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Hydrolase/hydrolase inhibitor PDB id
1waw
Jmol
Contents
Protein chain
366 a.a. *
Ligands
GOL ×3
0AR-DPR-ASP-HIS-
UN1
IPA
SO4
Waters ×346
* Residue conservation analysis
PDB id:
1waw
Name: Hydrolase/hydrolase inhibitor
Title: Specificity and affinity of natural product cyclopentapeptid inhibitor argadin against human chitinase
Structure: Chitotriosidase 1. Chain: a. Synonym: chitinase 1. Argadin. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes
Resolution:
1.75Å     R-factor:   0.174     R-free:   0.208
Authors: F.V.Rao,D.R.Houston,R.G.Boot,J.M.F.G.Aerts,M.Hodkinson,D.J.A K.Shiomi,S.Omura,D.M.F.Van Aalten
Key ref:
F.V.Rao et al. (2005). Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases. Chem Biol, 12, 65-76. PubMed id: 15664516 DOI: 10.1016/j.chembiol.2004.10.013
Date:
28-Oct-04     Release date:   28-Jan-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q13231  (CHIT1_HUMAN) -  Chitotriosidase-1
Seq:
Struc: 		466 a.a.
366 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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!
  Cellular component     extracellular region   3 terms 
  Biological process     metabolic process   7 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
DOI no: 10.1016/j.chembiol.2004.10.013 Chem Biol 12:65-76 (2005)
PubMed id: 15664516  
 
 
Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases.
F.V.Rao, D.R.Houston, R.G.Boot, J.M.Aerts, M.Hodkinson, D.J.Adams, K.Shiomi, S.Omura, D.M.van Aalten.
 
  ABSTRACT  
 
Family 18 chitinases play key roles in organisms ranging from bacteria to man. There is a need for specific, potent inhibitors to probe the function of these chitinases in different organisms. Such molecules could also provide leads for the development of chemotherapeuticals with fungicidal, insecticidal, or anti-inflammatory potential. Recently, two natural product peptides, argifin and argadin, have been characterized, which structurally mimic chitinase-chitooligosaccharide interactions and inhibit a bacterial chitinase in the nM-mM range. Here, we show that these inhibitors also act on human and Aspergillus fumigatus chitinases. The structures of these enzymes in complex with argifin and argadin, together with mutagenesis, fluorescence, and enzymology, reveal that subtle changes in the binding site dramatically affect affinity and selectivity. The data show that it may be possible to develop specific chitinase inhibitors based on the argifin/argadin scaffolds.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Chemical Structures of Argifin and Argadin 		Figure 2.
Figure 2. Structure of AfChiB1
 
  The above figures are reprinted by permission from Cell Press: Chem Biol (2005, 12, 65-76) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20142509 C.Gloeckner, A.L.Garner, F.Mersha, Y.Oksov, N.Tricoche, L.M.Eubanks, S.Lustigman, G.F.Kaufmann, and K.D.Janda (2010).
Repositioning of an existing drug for the neglected tropical disease Onchocerciasis.
  Proc Natl Acad Sci U S A, 107, 3424-3429.  
21168763 C.L.Rush, A.W.Schüttelkopf, R.Hurtado-Guerrero, D.E.Blair, A.F.Ibrahim, S.Desvergnes, I.M.Eggleston, and D.M.van Aalten (2010).
Natural product-guided discovery of a fungal chitinase inhibitor.
  Chem Biol, 17, 1275-1281.
PDB codes: 2xuc 2xvn 2xvp
20026047 H.C.Dorfmueller, and D.M.van Aalten (2010).
Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds.
  FEBS Lett, 584, 694-700.
PDB code: 2x0y
20553502 H.Tsuji, S.Nishimura, T.Inui, Y.Kado, K.Ishikawa, T.Nakamura, and K.Uegaki (2010).
Kinetic and crystallographic analyses of the catalytic domain of chitinase from Pyrococcus furiosus- the role of conserved residues in the active site.
  FEBS J, 277, 2683-2695.
PDB codes: 3a4w 3a4x 3afb
20829286 J.Yang, Z.Gan, Z.Lou, N.Tao, Q.Mi, L.Liang, Y.Sun, Y.Guo, X.Huang, C.Zou, Z.Rao, Z.Meng, and K.Q.Zhang (2010).
Crystal structure and mutagenesis analysis of chitinase CrChi1 from the nematophagous fungus Clonostachys rosea in complex with the inhibitor caffeine.
  Microbiology, 156, 3566-3574.
PDB codes: 3g6l 3g6m
  20454524 K.Ihrmark, N.Asmail, W.Ubhayasekera, P.Melin, J.Stenlid, and M.Karlsson (2010).
Comparative molecular evolution of trichoderma chitinases in response to mycoparasitic interactions.
  Evol Bioinform Online, 6, 1.  
19109670 M.J.Dixon, A.Nathubhai, O.A.Andersen, D.M.van Aalten, and I.M.Eggleston (2009).
Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold.
  Org Biomol Chem, 7, 259-268.  
19329983 T.Hirose, T.Sunazuka, A.Sugawara, A.Endo, K.Iguchi, T.Yamamoto, H.Ui, K.Shiomi, T.Watanabe, K.B.Sharpless, and S.Omura (2009).
Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry.
  J Antibiot (Tokyo), 62, 277-282.  
19703025 V.Kairys, M.K.Gilson, V.Lather, C.A.Schiffer, and M.X.Fernandes (2009).
Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.
  Chem Biol Drug Des, 74, 234-245.  
18975073 Y.Lü, H.Yang, H.Hu, Y.Wang, Z.Rao, and C.Jin (2009).
Mutation of Trp137 to glutamate completely removes transglycosyl activity associated with the Aspergillus fumigatus AfChiB1.
  Glycoconj J, 26, 525-534.  
18635010 A.Sadeghi-Khomami, M.D.Lumsden, and D.L.Jakeman (2008).
Glycosidase inhibition by macrolide antibiotics elucidated by STD-NMR spectroscopy.
  Chem Biol, 15, 739-749.  
18680214 C.Petter, C.Scholz, H.Wessner, G.Hansen, P.Henklein, T.Watanabe, and W.Höhne (2008).
Phage display screening for peptidic chitinase inhibitors.
  J Mol Recognit, 21, 401-409.  
18355718 H.Prinz (2008).
How to identify a pharmacophore.
  Chem Biol, 15, 207-208.  
18355729 O.A.Andersen, A.Nathubhai, M.J.Dixon, I.M.Eggleston, and D.M.van Aalten (2008).
Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin.
  Chem Biol, 15, 295-301.
PDB codes: 3ch9 3chc 3chd 3che 3chf
17524989 R.Hurtado-Guerrero, and D.M.van Aalten (2007).
Structure of Saccharomyces cerevisiae chitinase 1 and screening-based discovery of potent inhibitors.
  Chem Biol, 14, 589-599.
PDB codes: 2uy2 2uy3 2uy4 2uy5
16844689 A.W.Schüttelkopf, O.A.Andersen, F.V.Rao, M.Allwood, C.Lloyd, I.M.Eggleston, and D.M.van Aalten (2006).
Screening-based discovery and structural dissection of a novel family 18 chitinase inhibitor.
  J Biol Chem, 281, 27278-27285.
PDB code: 2iuz
16183021 F.V.Rao, O.A.Andersen, K.A.Vora, J.A.Demartino, and D.M.van Aalten (2005).
Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.
  Chem Biol, 12, 973-980.
PDB codes: 2a3a 2a3b 2a3c 2a3e
16193156 O.A.Andersen, M.J.Dixon, I.M.Eggleston, and D.M.van Aalten (2005).
Natural product family 18 chitinase inhibitors.
  Nat Prod Rep, 22, 563-579.  
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.