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PDBsum entry 1lq0

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protein links
Hydrolase PDB id
1lq0
Jmol
Contents
Protein chain
365 a.a. *
Waters ×134
* Residue conservation analysis
PDB id:
1lq0
Name: Hydrolase
Title: Crystal structure of human chitotriosidase at 2.2 angstrom resolution
Structure: Chitotriosidase. Chain: a. Fragment: residues 22-286. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.
Resolution:
2.20Å     R-factor:   0.212     R-free:   0.248
Authors: F.Fusetti,H.J.Rozeboom,B.W.Dijkstra
Key ref:
F.Fusetti et al. (2002). Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins. J Biol Chem, 277, 25537-25544. PubMed id: 11960986 DOI: 10.1074/jbc.M201636200
Date:
08-May-02     Release date:   29-Jul-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q13231  (CHIT1_HUMAN) -  Chitotriosidase-1
Seq:
Struc:
466 a.a.
365 a.a.
Key:    PfamA domain  PfamB 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!
  Biological process     carbohydrate metabolic process   2 terms 
  Biochemical function     hydrolase activity, hydrolyzing O-glycosyl compounds     2 terms  

 

 
DOI no: 10.1074/jbc.M201636200 J Biol Chem 277:25537-25544 (2002)
PubMed id: 11960986  
 
 
Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins.
F.Fusetti, H.von Moeller, D.Houston, H.J.Rozeboom, B.W.Dijkstra, R.G.Boot, J.M.Aerts, D.M.van Aalten.
 
  ABSTRACT  
 
Chitin hydrolases have been identified in a variety of organisms ranging from bacteria to eukaryotes. They have been proposed to be possible targets for the design of novel chemotherapeutics against human pathogens such as fungi and protozoan parasites as mammals were not thought to possess chitin-processing enzymes. Recently, a human chitotriosidase was described as a marker for Gaucher disease with plasma levels of the enzyme elevated up to 2 orders of magnitude. The chitotriosidase was shown to be active against colloidal chitin and is inhibited by the family 18 chitinase inhibitor allosamidin. Here, the crystal structure of the human chitotriosidase and complexes with a chitooligosaccharide and allosamidin are described. The structures reveal an elongated active site cleft, compatible with the binding of long chitin polymers, and explain the inactivation of the enzyme through an inherited genetic deficiency. Comparison with YM1 and HCgp-39 shows how the chitinase has evolved into these mammalian lectins by the mutation of key residues in the active site, tuning the substrate binding specificity. The soaking experiments with allosamidin and chitooligosaccharides give insight into ligand binding properties and allow the evaluation of differential binding and design of species-selective chitinase inhibitors.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Overview of chitotriosidase structure and comparison with other chitinases. A, stereo image of the final human chitotriosidase structure. The backbone is shown as a gray ribbon. The / domain is colored blue. Residues 344-372, which are deleted in the inherited mutated form of the enzyme, are colored green. Asp-136, Asp-138, and Glu-140 are shown as a sticks model with carbons colored yellow. Solvent-exposed aromatic side chains lining the active site cleft are shown as purple sticks. NAG[2], as seen in the complex (Table I), is shown in a sticks representation with orange carbon atoms. B, stereo image of the active site. The chitotriosidase backbone is shown as a gray ribbon. Solvent-exposed aromatics and residues interacting with NAG[2] are shown as sticks with carbons colored green for the apo structure and carbons colored purple for the chitotriosidase-NAG[2] complex. A simulated-annealing F[o] F[c], [calc] map for NAG[2] as observed in the chitotriosidase-NAG[2] complex is shown in blue, contoured at 3 . NAG[2] is shown in a sticks representation with orange carbon atoms. C, overall comparison with other chitinases. Molecular surfaces (calculated with PyMOL) are shown for currently known complexes of chitinases with chitooligosaccharides: hevamine with NAG[3] (31), ChiA with NAG [8] (32), ChiB with NAG[5] (29), and the human chitotriosidase with a model of NAG[9]. The TIM barrel core of the enzymes is orientated as in panel A. The catalytic glutamic acid is colored red, and exposed aromatic side chains lining the active site cleft are colored blue. The chitooligosaccharides are shown as sticks with green carbons.
Figure 3.
Fig. 3. Comparison of active site details and interaction with allosamidin. In A, the substrate binding pockets of the human chitotriosidase and YM1 are compared. Protein backbones are represented by a gray ribbon. A model of NAG[9], in equivalent position to that in Fig. 1, is shown as a sticks drawing with orange carbons. Side chains in the active site cleft are shown as sticks with green carbons, except for the catalytic glutamic acid, which is shown with yellow carbons. For YM1, non-conserved residues are shown with magenta carbons. In B, the interaction with allosamidin is compared for the chitotriosidase complex described here and the published C. immitis CTS1 chitinase complex (28). For both complexes, the enzyme backbone is shown as a gray ribbons model in stereo, and allosamidin is shown in a sticks representation with carbons colored orange. For the chitotriosidase, side chains contacting the inhibitor (defined as F[c], [calc] map (i.e. before the inclusion of any allosamidin model) is shown in magenta, contoured at 2.25 . For the CTS1-allosamidin complex, equivalent side chains are shown.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 25537-25544) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20843785 S.Gruber, G.Vaaje-Kolstad, F.Matarese, R.López-Mondéjar, C.P.Kubicek, and V.Seidl-Seiboth (2011).
Analysis of subgroup C of fungal chitinases containing chitin-binding and LysM modules in the mycoparasite Trichoderma atroviride.
  Glycobiology, 21, 122-133.  
21240541 T.Ohnuma, T.Numata, T.Osawa, M.Mizuhara, K.M.Vårum, and T.Fukamizo (2011).
Crystal structure and mode of action of a class V chitinase from Nicotiana tabacum.
  Plant Mol Biol, 75, 291-304.
PDB codes: 3alf 3alg
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.  
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
  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.  
19472335 J.E.Urch, R.Hurtado-Guerrero, D.Brosson, Z.Liu, V.G.Eijsink, C.Texier, and D.M.van Aalten (2009).
Structural and functional characterization of a putative polysaccharide deacetylase of the human parasite Encephalitozoon cuniculi.
  Protein Sci, 18, 1197-1209.
PDB code: 2vyo
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.  
19681676 R.G.Boot, M.J.van Breemen, W.Wegdam, R.R.Sprenger, S.de Jong, D.Speijer, C.E.Hollak, L.van Dussen, H.C.Hoefsloot, A.K.Smilde, C.G.de Koster, J.P.Vissers, and J.M.Aerts (2009).
Gaucher disease: a model disorder for biomarker discovery.
  Expert Rev Proteomics, 6, 411-419.  
19029990 D.M.Mosser, and J.P.Edwards (2008).
Exploring the full spectrum of macrophage activation.
  Nat Rev Immunol, 8, 958-969.  
18342250 Q.Zhu, Y.Arakane, D.Banerjee, R.W.Beeman, K.J.Kramer, and S.Muthukrishnan (2008).
Domain organization and phylogenetic analysis of the chitinase-like family of proteins in three species of insects.
  Insect Biochem Mol Biol, 38, 452-466.  
18342251 Q.Zhu, Y.Arakane, R.W.Beeman, K.J.Kramer, and S.Muthukrishnan (2008).
Characterization of recombinant chitinase-like proteins of Drosophila melanogaster and Tribolium castaneum.
  Insect Biochem Mol Biol, 38, 467-477.  
17453243 A.Giansanti, M.Bocchieri, V.Rosato, and S.Musumeci (2007).
A fine functional homology between chitinases from host and parasite is relevant for malaria transmissibility.
  Parasitol Res, 101, 639-645.  
17765019 A.J.Hall, R.J.Quinnell, A.Raiko, M.Lagog, P.Siba, S.Morroll, and F.H.Falcone (2007).
Chitotriosidase deficiency is not associated with human hookworm infection in a Papua New Guinean population.
  Infect Genet Evol, 7, 743-747.  
17720922 A.P.Bussink, D.Speijer, J.M.Aerts, and R.G.Boot (2007).
Evolution of mammalian chitinase(-like) members of family 18 glycosyl hydrolases.
  Genetics, 177, 959-970.  
  17401190 A.S.Ethayathulla, D.B.Srivastava, J.Kumar, K.Saravanan, S.Bilgrami, S.Sharma, P.Kaur, A.Srinivasan, and T.P.Singh (2007).
Structure of the buffalo secretory signalling glycoprotein at 2.8 A resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 258-265.
PDB code: 2o9o
  19662198 J.Kzhyshkowska, A.Gratchev, and S.Goerdt (2007).
Human chitinases and chitinase-like proteins as indicators for inflammation and cancer.
  Biomark Insights, 2, 128-146.  
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
17543889 Zaheer-ul-Haq, P.Dalal, N.N.Aronson, and J.D.Madura (2007).
Family 18 chitolectins: comparison of MGP40 and HUMGP39.
  Biochem Biophys Res Commun, 359, 221-226.  
16929095 J.Kumar, A.S.Ethayathulla, D.B.Srivastava, S.Sharma, S.B.Singh, A.Srinivasan, M.P.Yadav, and T.P.Singh (2006).
Structure of a bovine secretory signalling glycoprotein (SPC-40) at 2.1 Angstrom resolution.
  Acta Crystallogr D Biol Crystallogr, 62, 953-963.
PDB code: 2esc
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.  
16848812 L.Malaguarnera, M.D.Rosa, A.M.Zambito, N.dell'Ombra, R.D.Marco, and M.Malaguarnera (2006).
Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution.
  Am J Gastroenterol, 101, 2060-2069.  
16825325 L.Malaguarnera, M.Di Rosa, A.M.Zambito, N.dell'Ombra, F.Nicoletti, and M.Malaguarnera (2006).
Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease.
  Gut, 55, 1313-1320.  
16685709 S.Pyrpassopoulos, M.Vlassi, A.Tsortos, Y.Papanikolau, K.Petratos, C.E.Vorgias, and G.Nounesis (2006).
Equilibrium heat-induced denaturation of chitinase 40 from Streptomyces thermoviolaceus.
  Proteins, 64, 513-523.  
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
15899671 M.Di Rosa, M.Musumeci, A.Scuto, S.Musumeci, and L.Malaguarnera (2005).
Effect of interferon-gamma, interleukin-10, lipopolysaccharide and tumor necrosis factor-alpha on chitotriosidase synthesis in human macrophages.
  Clin Chem Lab Med, 43, 499-502.  
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.  
16005164 T.Zheng, M.Rabach, N.Y.Chen, L.Rabach, X.Hu, J.A.Elias, and Z.Zhu (2005).
Molecular cloning and functional characterization of mouse chitotriosidase.
  Gene, 357, 37-46.  
14717693 B.Synstad, S.Gåseidnes, D.M.Van Aalten, G.Vriend, J.E.Nielsen, and V.G.Eijsink (2004).
Mutational and computational analysis of the role of conserved residues in the active site of a family 18 chitinase.
  Eur J Biochem, 271, 253-262.  
15271211 L.Shi, and S.M.Paskewitz (2004).
Identification and molecular characterization of two immune-responsive chitinase-like proteins from Anopheles gambiae.
  Insect Mol Biol, 13, 387-398.  
14646200 M.Ujita, K.Sakai, K.Hamazaki, M.Yoneda, S.Isomura, and A.Hara (2003).
Carbohydrate binding specificity of the recombinant chitin-binding domain of human macrophage chitinase.
  Biosci Biotechnol Biochem, 67, 2402-2407.  
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.