PDBsum entry 2a3b

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Hydrolase PDB id
Protein chains
394 a.a. *
SO4 ×12
CFF ×6
Waters ×969
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of aspergillus fumigatus chitinase b1 in complex with caffeine
Structure: Chitinase. Chain: a, b. Synonym: chitinase b1. Engineered: yes
Source: Aspergillus fumigatus. Organism_taxid: 5085. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
1.90Å     R-factor:   0.176     R-free:   0.202
Authors: F.V.Rao,O.A.Andersen,K.A.Vora,J.A.Demartino,D.M.F.Van Aalten
Key ref:
F.V.Rao et al. (2005). Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes. Chem Biol, 12, 973-980. PubMed id: 16183021 DOI: 10.1016/j.chembiol.2005.07.009
24-Jun-05     Release date:   27-Sep-05    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q873X9  (Q873X9_ASPFM) -  Chitinase
433 a.a.
394 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   3 terms 
  Biochemical function     hydrolase activity     4 terms  


DOI no: 10.1016/j.chembiol.2005.07.009 Chem Biol 12:973-980 (2005)
PubMed id: 16183021  
Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.
F.V.Rao, O.A.Andersen, K.A.Vora, J.A.Demartino, D.M.van Aalten.
Family 18 chitinases play key roles in a range of pathogenic organisms and are overexpressed in the asthmatic lung. By screening a library of marketed drug molecules, we have identified methylxanthine derivatives as possible inhibitor leads. These derivatives, theophylline, caffeine, and pentoxifylline, are used therapeutically as antiinflammatory agents, with pleiotropic mechanisms of action. Here it is shown that they are also competitive inhibitors against a fungal family 18 chitinase, with pentoxifylline being the most potent (K(i) of 37 microM). Crystallographic analysis of chitinase-inhibitor complexes revealed specific interactions with the active site, mimicking the reaction intermediate analog, allosamidin. Mutagenesis identified the key active site residues, conserved in mammalian chitinases, which contribute to inhibitor affinity. Enzyme assays also revealed that these methylxanthines are active against human chitinases.
  Selected figure(s)  
Figure 1.
Figure 1. Characterization of Theophylline, Caffeine, and Pentoxifylline Inhibition
Figure 2.
Figure 2. Structures of the AfChiB1 Inhibitor Complexes
  The above figures are reprinted by permission from Cell Press: Chem Biol (2005, 12, 973-980) copyright 2005.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21283705 W.Gu, J.Yang, Z.Lou, L.Liang, Y.Sun, J.Huang, X.Li, Y.Cao, Z.Meng, and K.Q.Zhang (2011).
Structural Basis of Enzymatic Activity for the Ferulic Acid Decarboxylase (FADase) from Enterobacter sp. Px6-4.
  PLoS One, 6, e16262.
PDB codes: 3nx1 3nx2
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
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
19908331 K.Eurich, M.Segawa, S.Toei-Shimizu, and E.Mizoguchi (2009).
Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells.
  World J Gastroenterol, 15, 5249-5259.  
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.  
18626709 Y.Han, B.Yang, F.Zhang, X.Miao, and Z.Li (2009).
Characterization of Antifungal Chitinase from Marine Streptomyces sp. DA11 Associated with South China Sea Sponge Craniella Australiensis.
  Mar Biotechnol (NY), 11, 132-140.  
  19342787 Z.Gan, J.Yang, N.Tao, Z.Lou, Q.Mi, Z.Meng, and K.Q.Zhang (2009).
Crystallization and preliminary crystallographic analysis of a chitinase from Clonostachys rosea.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 386-388.  
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
16761182 L.Duo-Chuan (2006).
Review of fungal chitinases.
  Mycopathologia, 161, 345-360.  
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