PDBsum entry 1hkk

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Hydrolase PDB id
Protein chain
364 a.a. *
_ZN ×3
Waters ×253
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: High resoultion crystal structure of human chitinase in complex with allosamidin
Structure: Chitotriosidase-1. Chain: a. Synonym: chitinase-1. Other_details: allosamidin
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: macrophages
1.85Å     R-factor:   0.179     R-free:   0.189
Authors: F.V.Rao,D.R.Houston,R.G.Boot,J.M.F.G.Aerts,S.Sakuda, D.M.F.Van Aalten
Key ref:
F.V.Rao et al. (2003). Crystal structures of allosamidin derivatives in complex with human macrophage chitinase. J Biol Chem, 278, 20110-20116. PubMed id: 12639956 DOI: 10.1074/jbc.M300362200
10-Mar-03     Release date:   11-Mar-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q13231  (CHIT1_HUMAN) -  Chitotriosidase-1
466 a.a.
364 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - 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  


DOI no: 10.1074/jbc.M300362200 J Biol Chem 278:20110-20116 (2003)
PubMed id: 12639956  
Crystal structures of allosamidin derivatives in complex with human macrophage chitinase.
F.V.Rao, D.R.Houston, R.G.Boot, J.M.Aerts, S.Sakuda, D.M.van Aalten.
The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structure-based design of specific allosamidin derivatives.
  Selected figure(s)  
Figure 3.
FIG. 3. Complexes with allosamidin derivatives. Stereo images of the final structures of the human chitinase in complex with allosamidin and its derivatives are shown. Side chains interacting with the allosamidins (also indicated in Fig. 2) are shown in a sticks representation. The allosamidins are shown as a sticks model with orange carbons. Water molecules involved in allosamidin hydrogen bonds are shown as red spheres. Hydrogen bonds are shown as dotted green lines and are listed in Table IV. The unbiased F[o] - F[c], [calc] maps before inclusion of models for the inhibitors in the refinement are shown in magenta, contoured at 2.25 .
Figure 4.
FIG. 4. Sequence conservation in the active site. Stereo image of the molecular surfaces calculated from HCHT in the HCHT·ALLO complex and hevamine in the hevamine·ALLO complex (18) is shown. Blue surface corresponds to conserved residues (Fig. 2), which are also shown as a sticks model. ALLO is shown as a sticks model with green carbons. The / domain, absent in hevamine, is indicated in HCHT.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 20110-20116) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21044846 A.W.Schüttelkopf, L.Gros, D.E.Blair, J.A.Frearson, D.M.van Aalten, and I.H.Gilbert (2010).
Acetazolamide-based fungal chitinase inhibitors.
  Bioorg Med Chem, 18, 8334-8340.
PDB code: 2xtk
20084296 H.Li, and L.H.Greene (2010).
Sequence and structural analysis of the chitinase insertion domain reveals two conserved motifs involved in chitin-binding.
  PLoS One, 5, e8654.  
  19241384 A.M.Olland, J.Strand, E.Presman, R.Czerwinski, D.Joseph-McCarthy, R.Krykbaev, G.Schlingmann, R.Chopra, L.Lin, M.Fleming, R.Kriz, M.Stahl, W.Somers, L.Fitz, and L.Mosyak (2009).
Triad of polar residues implicated in pH specificity of acidic mammalian chitinase.
  Protein Sci, 18, 569-578.
PDB codes: 3fxy 3fy1
19725875 A.P.Bussink, M.Verhoek, J.Vreede, K.Ghauharali-van der Vlugt, W.E.Donker-Koopman, R.R.Sprenger, C.E.Hollak, J.M.Aerts, and R.G.Boot (2009).
Common G102S polymorphism in chitotriosidase differentially affects activity towards 4-methylumbelliferyl substrates.
  FEBS J, 276, 5678-5688.  
19681676 R.G.Boot, M.J.van Breemen, W.Wegdam, R.R.Sprenger, Jong, D.Speijer, C.E.Hollak, L.van Dussen, H.C.Hoefsloot, A.K.Smilde, Koster, J.P.Vissers, and J.M.Aerts (2009).
Gaucher disease: a model disorder for biomarker discovery.
  Expert Rev Proteomics, 6, 411-419.  
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.  
19085022 Y.S.Zhao, Q.C.Zheng, H.X.Zhang, H.Y.Chu, and C.C.Sun (2009).
Analysis of a three-dimensional structure of human acidic mammalian chitinase obtained by homology modeling and ligand binding studies.
  J Mol Model, 15, 499-505.  
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.  
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
16526080 F.H.Cederkvist, A.D.Zamfir, S.Bahrke, V.G.Eijsink, M.Sørlie, J.Peter-Katalinić, and M.G.Peter (2006).
Identification of a high-affinity-binding oligosaccharide by (+) nanoelectrospray quadrupole time-of-flight tandem mass spectrometry of a noncovalent enzyme-ligand complex.
  Angew Chem Int Ed Engl, 45, 2429-2434.  
16763917 J.M.Aerts, C.E.Hollak, R.G.Boot, J.E.Groener, and M.Maas (2006).
Substrate reduction therapy of glycosphingolipid storage disorders.
  J Inherit Metab Dis, 29, 449-456.  
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.  
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 code is shown on the right.