PDBsum entry 1nwu

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Signaling protein PDB id
Protein chain
362 a.a. *
Waters ×419
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of human cartilage gp39 (hc-gp39) in compl chitotetraose
Structure: Chitinase-3 like protein 1. Chain: a, b, c, d. Synonym: cartilage glycoprotein-39, gp-39, 39 kda synovial ykl-40. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: synovial cells, articular chondrocytes. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: mammalian cho cells
2.20Å     R-factor:   0.225     R-free:   0.245
Authors: F.Fusetti,T.Pijning,K.H.Kalk,E.Bos,B.W.Dijkstra
Key ref:
F.Fusetti et al. (2003). Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem, 278, 37753-37760. PubMed id: 12851408 DOI: 10.1074/jbc.M303137200
06-Feb-03     Release date:   26-Aug-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P36222  (CH3L1_HUMAN) -  Chitinase-3-like protein 1
383 a.a.
362 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   7 terms 
  Biological process     cellular response to tumor necrosis factor   18 terms 
  Biochemical function     extracellular matrix structural constituent     5 terms  


DOI no: 10.1074/jbc.M303137200 J Biol Chem 278:37753-37760 (2003)
PubMed id: 12851408  
Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39.
F.Fusetti, T.Pijning, K.H.Kalk, E.Bos, B.W.Dijkstra.
The human cartilage glycoprotein-39 (HCgp-39 or YKL40) is expressed by synovial cells and macrophages during inflammation. Its precise physiological role is unknown. However, it has been proposed that HCgp-39 acts as an autoantigen in rheumatoid arthritis, and high expression levels have been associated with cancer development. HCgp-39 shares high sequence homology with family 18 chitinases, and although it binds to chitin it lacks enzymatic activity. The crystal structure of HCgp-39 shows that the protein displays a (beta/alpha)8-barrel fold with an insertion of an alpha + beta domain. A 43-A long carbohydrate-binding cleft is present at the C-terminal side of the beta-strands in the (beta/alpha)8 barrel. Binding of chitin fragments of different lengths identified nine sugar-binding subsites in the groove. Protein-carbohydrate interactions are mainly mediated by stacking of side chains of aromatic amino acid residues. Surprisingly, the specificity of chitin binding to HCgp-39 depends on the length of the oligosaccharide. Although chitin disaccharides tend to occupy the distal subsites, longer chains bind preferably to the central subsites in the groove. Despite the absence of enzymatic activity, long chitin fragments are distorted upon binding, with the GlcNAc at subsite -1 in a boat conformation, similar to what has been observed in chitinases. The presence of chitin in the human body has never been documented so far. However, the binding features observed in the complex structures suggest that either chitin or a closely related oligosaccharide could act as the physiological ligand for HCgp-39.
  Selected figure(s)  
Figure 3.
FIG. 3. Model structure of HCgp-39 with a long chitin fragment. a, stereo view of the binding site showing the structure of a bound chitin oligosaccharide and the lining of aromatic amino acids. The "boat" structure of GlcNAc is visible in the -1 subsite. The F[o] -F[c] electron density map was calculated with the HCgp-39-(GlcNAc)[5] crystallographic data prior to model building of the ligand. (GlcNAc)[5] is shown in black in ball-and-stick representation; the HCgp-39 structure is shown as a ribbon representation in light gray. The aromatic residues lining the carbohydrate-binding site are shown in ball-and-stick representation. The figure was generated using the programs BOBSCRIPT (59) and RASTER-3D (58). b, schematic representation of the chitin-binding site showing protein-carbohydrate interactions at subsites -3 to +3, -6, and -5. The bound chitin and the amino acid side chains are shown in thick and thin black lines, respectively. The hydrogen-bonding interactions are shown as red dashed lines with atomic distances in Å. Amino acid residues having hydrophobic interactions with the bound chitin are schematically drawn as brown half-circles. Water molecules are shown as blue spheres. The figure was generated with the program LIGPLOT (60) followed by manual editing.
Figure 4.
FIG. 4. Surface representation of the structures of native HCgp-39 (a) and of HCgp-39 in complex with chito-oligosaccharides (b). The protein surface is colored as follows: aromatic amino acids are shown in cyan, Trp99 is depicted in violet, the putative heparin-binding site GRRDKQH (residues 143-149) is colored blue, and the epitope 259-271 is colored in red (residues 259-265) and orange (residues 266-271). The bound (GlcNAc)[5] and (GlcNAc)[2] are shown in white and pink sticks, respectively. The figure was generated with the program PyMOL (61).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 37753-37760) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20506295 B.M.Ku, Y.K.Lee, J.Ryu, J.Y.Jeong, J.Choi, K.M.Eun, H.Y.Shin, D.G.Kim, E.M.Hwang, J.C.Yoo, J.Y.Park, G.S.Roh, H.J.Kim, G.J.Cho, W.S.Choi, S.H.Paek, and S.S.Kang (2011).
CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells.
  Int J Cancer, 128, 1316-1326.  
21054166 C.G.Lee, C.A.Da Silva, C.S.Dela Cruz, F.Ahangari, B.Ma, M.J.Kang, C.H.He, S.Takyar, and J.A.Elias (2011).
Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury.
  Annu Rev Physiol, 73, 479-501.  
21530869 J.Cunningham, K.Basu, R.Tavendale, C.N.Palmer, H.Smith, and S.Mukhopadhyay (2011).
The CHI3L1 rs4950928 polymorphism is associated with asthma-related hospital admissions in children and young adults.
  Ann Allergy Asthma Immunol, 106, 381-386.  
21274454 M.Kanneganti, M.Mino-Kenudson, and E.Mizoguchi (2011).
Animal models of colitis-associated carcinogenesis.
  J Biomed Biotechnol, 2011, 342637.  
20559485 B.B.Aam, E.B.Heggset, A.L.Norberg, M.Sørlie, K.M.Vårum, and V.G.Eijsink (2010).
Production of chitooligosaccharides and their potential applications in medicine.
  Mar Drugs, 8, 1482-1517.  
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.  
19259344 C.G.Lee (2009).
Chitin, chitinases and chitinase-like proteins in allergic inflammation and tissue remodeling.
  Yonsei Med J, 50, 22-30.  
19930630 C.N.Rathcke, and H.Vestergaard (2009).
YKL-40 - an emerging biomarker in cardiovascular disease and diabetes.
  Cardiovasc Diabetol, 8, 61.  
19792974 J.S.Johansen, N.A.Schultz, and B.V.Jensen (2009).
Plasma YKL-40: a potential new cancer biomarker?
  Future Oncol, 5, 1065-1082.  
19596709 M.Lienemann, H.Boer, A.Paananen, S.Cottaz, and A.Koivula (2009).
Toward understanding of carbohydrate binding and substrate specificity of a glycosyl hydrolase 18 family (GH-18) chitinase from Trichoderma harzianum.
  Glycobiology, 19, 1116-1126.  
19442276 M.Pasztoi, G.Nagy, P.Geher, T.Lakatos, K.Toth, K.Wellinger, P.Pocza, B.Gyorgy, M.C.Holub, A.Kittel, K.Paloczy, M.Mazan, P.Nyirkos, A.Falus, and E.I.Buzas (2009).
Gene expression and activity of cartilage-degrading glycosidases in human rheumatoid arthritis and osteoarthritis synovial fibroblasts.
  Arthritis Res Ther, 11, R68.  
19767768 R.Shao, K.Hamel, L.Petersen, Q.J.Cao, R.B.Arenas, C.Bigelow, B.Bentley, and W.Yan (2009).
YKL-40, a secreted glycoprotein, promotes tumor angiogenesis.
  Oncogene, 28, 4456-4468.  
18182077 A.K.Mylin, N.Abildgaard, J.S.Johansen, N.F.Andersen, L.Heickendorff, T.Standal, P.Gimsing, and L.M.Knudsen (2008).
High serum YKL-40 concentration is associated with severe bone disease in newly diagnosed multiple myeloma patients.
  Eur J Haematol, 80, 310-317.  
18157633 A.Roslind, A.S.Knoop, M.B.Jensen, J.S.Johansen, D.L.Nielsen, P.A.Price, and E.Balslev (2008).
YKL-40 protein expression is not a prognostic marker in patients with primary breast cancer.
  Breast Cancer Res Treat, 112, 275-285.  
17957792 A.Roslind, J.S.Johansen, I.J.Christensen, K.Kiss, E.Balslev, D.L.Nielsen, J.Bentzen, P.A.Price, and E.Andersen (2008).
High serum levels of YKL-40 in patients with squamous cell carcinoma of the head and neck are associated with short survival.
  Int J Cancer, 122, 857-863.  
  18556781 D.Bonneh-Barkay, S.J.Bissel, G.Wang, K.N.Fish, G.C.Nicholl, S.W.Darko, R.Medina-Flores, M.Murphey-Corb, P.A.Rajakumar, J.Nyaundi, J.W.Mellors, R.Bowser, and C.A.Wiley (2008).
YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor.
  Am J Pathol, 173, 130-143.  
18490894 M.Kawada, C.C.Chen, A.Arihiro, K.Nagatani, T.Watanabe, and E.Mizoguchi (2008).
Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein.
  Lab Invest, 88, 883-895.  
17645792 A.M.Boots, H.Hubers, M.Kouwijzer, L.den Hoed-van Zandbrink, B.M.Westrek-Esselink, C.van Doorn, R.Stenger, E.S.Bos, M.J.van Lierop, G.F.Verheijden, C.M.Timmers, and C.J.van Staveren (2007).
Identification of an altered peptide ligand based on the endogenously presented, rheumatoid arthritis-associated, human cartilage glycoprotein-39(263-275) epitope: an MHC anchor variant peptide for immune modulation.
  Arthritis Res Ther, 9, R71.  
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
17496346 E.Mizoguchi, and A.Mizoguchi (2007).
Is the sugar always sweet in intestinal inflammation?
  Immunol Res, 37, 47-60.  
17594485 J.D.Funkhouser, and N.N.Aronson (2007).
Chitinase family GH18: evolutionary insights from the genomic history of a diverse protein family.
  BMC Evol Biol, 7, 96.  
17372347 J.Kumar, A.S.Ethayathulla, D.B.Srivastava, N.Singh, S.Sharma, P.Kaur, A.Srinivasan, and T.P.Singh (2007).
Carbohydrate-binding properties of goat secretory glycoprotein (SPG-40) and its functional implications: structures of the native glycoprotein and its four complexes with chitin-like oligosaccharides.
  Acta Crystallogr D Biol Crystallogr, 63, 437-446.
PDB codes: 2dsz 2dt0 2dt1 2dt2 2dt3
  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.  
17227236 J.S.Johansen, B.V.Jensen, A.Roslind, and P.A.Price (2007).
Is YKL-40 a new therapeutic target in cancer?
  Expert Opin Ther Targets, 11, 219-234.  
17392594 M.Kawada, Y.Hachiya, A.Arihiro, and E.Mizoguchi (2007).
Role of mammalian chitinases in inflammatory conditions.
  Keio J Med, 56, 21-27.  
17242979 M.Ringsholt, E.V.Høgdall, J.S.Johansen, P.A.Price, and L.H.Christensen (2007).
YKL-40 protein expression in normal adult human tissues--an immunohistochemical study.
  J Mol Histol, 38, 33-43.  
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.  
16930142 A.K.Mylin, T.Rasmussen, J.S.Johansen, L.M.Knudsen, P.H.Nørgaard, S.Lenhoff, I.M.Dahl, and H.E.Johnsen (2006).
Serum YKL-40 concentrations in newly diagnosed multiple myeloma patients and YKL-40 expression in malignant plasma cells.
  Eur J Haematol, 77, 416-424.  
16472595 E.Mizoguchi (2006).
Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells.
  Gastroenterology, 130, 398-411.  
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
15771622 N.Junker, J.S.Johansen, L.T.Hansen, E.L.Lund, and P.E.Kristjansen (2005).
Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells.
  Cancer Sci, 96, 183-190.  
15059280 K.Dasuri, M.Antonovici, K.Chen, K.Wong, K.Standing, W.Ens, H.El-Gabalawy, and J.A.Wilkins (2004).
The synovial proteome: analysis of fibroblast-like synoviocytes.
  Arthritis Res Ther, 6, R161-R168.  
15361235 R.M.Maizels, A.Balic, N.Gomez-Escobar, M.Nair, M.D.Taylor, and J.E.Allen (2004).
Helminth parasites--masters of regulation.
  Immunol Rev, 201, 89.  
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.