spacer
spacer
Go to PDB code: 
protein ligands links
Hydrolase, hydrolase inhibitor PDB id
1mz6
Jmol
Contents
Protein chain
620 a.a. *
Ligands
NAG ×5
DAN
Waters ×40
* Residue conservation analysis
PDB id:
1mz6
Name: Hydrolase, hydrolase inhibitor
Title: Trypanosoma rangeli sialidase in complex with the inhibitor
Structure: Sialidase. Chain: a. Fragment: mature sialidase. Ec: 3.2.1.18
Source: Trypanosoma rangeli. Organism_taxid: 5698
Resolution:
2.90Å     R-factor:   0.209     R-free:   0.287
Authors: A.Buschiazzo,G.A.Tavares,O.Campetella,S.Spinelli,M.L.Cremona M.F.Amaya,A.C.C.Frasch,P.M.Alzari
Key ref:
A.Buschiazzo et al. (2000). Structural basis of sialyltransferase activity in trypanosomal sialidases. EMBO J, 19, 16-24. PubMed id: 10619840 DOI: 10.1093/emboj/19.1.16
Date:
05-Oct-02     Release date:   16-Oct-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O44049  (O44049_TRYRA) -  Sialidase (Precursor)
Seq:
Struc: 		 
Seq:
Struc: 		660 a.a.
620 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.2.1.18  - Exo-alpha-sialidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   2 terms 
  Biochemical function     hydrolase activity     6 terms  

 

 
DOI no: 10.1093/emboj/19.1.16 EMBO J 19:16-24 (2000)
PubMed id: 10619840  
 
 
Structural basis of sialyltransferase activity in trypanosomal sialidases.
A.Buschiazzo, G.A.Tavares, O.Campetella, S.Spinelli, M.L.Cremona, G.París, M.F.Amaya, A.C.Frasch, P.M.Alzari.
 
  ABSTRACT  
 
The intracellular parasite Trypanosoma cruzi, the etiological agent of Chagas disease, sheds a developmentally regulated surface trans-sialidase, which is involved in key aspects of parasite-host cell interactions. Although it shares a common active site architecture with bacterial neuraminidases, the T.cruzi enzyme behaves as a highly efficient sialyltransferase. Here we report the crystal structure of the closely related Trypanosoma rangeli sialidase and its complex with inhibitor. The enzyme folds into two distinct domains: a catalytic beta-propeller fold tightly associated with a lectin-like domain. Comparison with the modeled structure of T.cruzi trans-sialidase and mutagenesis experiments allowed the identification of amino acid substitutions within the active site cleft that modulate sialyltransferase activity and suggest the presence of a distinct binding site for the acceptor carbohydrate. The structures of the Trypanosoma enzymes illustrate how a glycosidase scaffold can achieve efficient glycosyltransferase activity and provide a framework for structure-based drug design.
 
  Selected figure(s)  
 
Figure 3.
Figure 3 Structure of TrSA in complex with DANA. (A) Final electron density map at 2.9 Šresolution (contoured at 1.5 ). (B) Top view of the active site pocket with the bound inhibitor (in yellow). (C) Scheme showing enzyme–inhibitor hydrogen bonding interactions. 		Figure 5.
Figure 5 The active site cleft of trypanosomal sialidases. (A) Structure of the TrSA–inhibitor complex colored according to charge. (B) Model of TcTS with bound sialic acid. Amino acid differences between TrSA and TcTS at the molecular surface (colored in red) involve potential substrate-contacting residues Ser120-Tyr, Gln284-Pro, Gly249-Tyr, Asp363-Glu and Phe59-Asn. Putative binding sites for the sialic acid donor and acceptor substrates, respectively, close to the aromatic side chains of Trp313 and Tyr120 are indicated by dashed arrows (see the text for details).
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2000, 19, 16-24) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21253654 J.A.Harrison, K.P.Kartha, E.J.Fournier, T.L.Lowary, C.Malet, U.J.Nilsson, O.Hindsgaul, S.Schenkman, J.H.Naismith, and R.A.Field (2011).
Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries.
  Org Biomol Chem, 9, 1653-1660.  
20124697 E.C.Schulz, P.Neumann, R.Gerardy-Schahn, G.M.Sheldrick, and R.Ficner (2010).
Structure analysis of endosialidase NF at 0.98 A resolution.
  Acta Crystallogr D Biol Crystallogr, 66, 176-180.  
19594936 E.M.Quistgaard, and S.S.Thirup (2009).
Sequence and structural analysis of the Asp-box motif and Asp-box beta-propellers; a widespread propeller-type characteristic of the Vps10 domain family and several glycoside hydrolase families.
  BMC Struct Biol, 9, 46.  
19920252 M.V.Chuenkova, and M.PereiraPerrin (2009).
Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy.
  Sci Signal, 2, ra74.  
19216574 O.Demir, and A.E.Roitberg (2009).
Modulation of catalytic function by differential plasticity of the active site: case study of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase.
  Biochemistry, 48, 3398-3406.  
18949046 L.Ratier, M.Urrutia, G.Paris, L.Zarebski, A.C.Frasch, and F.A.Goldbaum (2008).
Relevance of the diversity among members of the Trypanosoma cruzi trans-sialidase family analyzed with camelids single-domain antibodies.
  PLoS ONE, 3, e3524.  
18218621 S.L.Newstead, J.A.Potter, J.C.Wilson, G.Xu, C.H.Chien, A.G.Watts, S.G.Withers, and G.L.Taylor (2008).
The structure of Clostridium perfringens NanI sialidase and its catalytic intermediates.
  J Biol Chem, 283, 9080-9088.
PDB codes: 2bf6 2vk5 2vk6 2vk7
16956887 G.N.Montagna, J.E.Donelson, and A.C.Frasch (2006).
Procyclic Trypanosoma brucei expresses separate sialidase and trans-sialidase enzymes on its surface membrane.
  J Biol Chem, 281, 33949-33958.  
15898128 L.B.Buratai, A.J.Nok, S.Ibrahim, I.A.Umar, and K.A.Esievo (2006).
Characterization of sialidase from bloodstream forms of Trypanosoma vivax.
  Cell Biochem Funct, 24, 71-77.  
16495535 P.N.Nde, K.J.Simmons, Y.Y.Kleshchenko, S.Pratap, M.F.Lima, and F.Villalta (2006).
Silencing of the laminin gamma-1 gene blocks Trypanosoma cruzi infection.
  Infect Immun, 74, 1643-1648.  
15827656 B.Neubacher, D.Schmidt, P.Ziegelmuller, and J.Thiem (2005).
Preparation of sialylated oligosaccharides employing recombinant trans-sialidase from Trypanosoma cruzi.
  Org Biomol Chem, 3, 1551-1556.  
15608653 K.Stummeyer, A.Dickmanns, M.Mühlenhoff, R.Gerardy-Schahn, and R.Ficner (2005).
Crystal structure of the polysialic acid-degrading endosialidase of bacteriophage K1F.
  Nat Struct Mol Biol, 12, 90-96.
PDB codes: 1v0e 1v0f
15501818 L.M.Chavas, C.Tringali, P.Fusi, B.Venerando, G.Tettamanti, R.Kato, E.Monti, and S.Wakatsuki (2005).
Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition.
  J Biol Chem, 280, 469-475.
PDB codes: 1snt 1so7 1vcu
15618155 M.V.Tribulatti, J.Mucci, N.Van Rooijen, M.S.Leguizamón, and O.Campetella (2005).
The trans-sialidase from Trypanosoma cruzi induces thrombocytopenia during acute Chagas' disease by reducing the platelet sialic acid contents.
  Infect Immun, 73, 201-207.  
15893670 P.Yuan, T.B.Thompson, B.A.Wurzburg, R.G.Paterson, R.A.Lamb, and T.S.Jardetzky (2005).
Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose.
  Structure, 13, 803-815.
PDB codes: 1z4v 1z4w 1z4x 1z4y 1z4z 1z50
16239725 S.L.Newstead, J.N.Watson, A.J.Bennet, and G.Taylor (2005).
Galactose recognition by the carbohydrate-binding module of a bacterial sialidase.
  Acta Crystallogr D Biol Crystallogr, 61, 1483-1491.
PDB codes: 2bq9 2bzd
14730352 C.P.Chiu, A.G.Watts, L.L.Lairson, M.Gilbert, D.Lim, W.W.Wakarchuk, S.G.Withers, and N.C.Strynadka (2004).
Structural analysis of the sialyltransferase CstII from Campylobacter jejuni in complex with a substrate analog.
  Nat Struct Mol Biol, 11, 163-170.
PDB codes: 1ro7 1ro8
15226294 I.Moustafa, H.Connaris, M.Taylor, V.Zaitsev, J.C.Wilson, M.J.Kiefel, M.von Itzstein, and G.Taylor (2004).
Sialic acid recognition by Vibrio cholerae neuraminidase.
  J Biol Chem, 279, 40819-40826.
PDB codes: 1w0o 1w0p
15130470 M.F.Amaya, A.G.Watts, I.Damager, A.Wehenkel, T.Nguyen, A.Buschiazzo, G.Paris, A.C.Frasch, S.G.Withers, and P.M.Alzari (2004).
Structural insights into the catalytic mechanism of Trypanosoma cruzi trans-sialidase.
  Structure, 12, 775-784.
PDB codes: 1s0i 1s0j 1s0k 2ah2
15502328 S.Newstead, C.H.Chien, M.Taylor, and G.Taylor (2004).
Crystallization and atomic resolution X-ray diffraction of the catalytic domain of the large sialidase, nanI, from Clostridium perfringens.
  Acta Crystallogr D Biol Crystallogr, 60, 2063-2066.  
14747991 T.Pons, D.G.Naumoff, C.Martínez-Fleites, and L.Hernández (2004).
Three acidic residues are at the active site of a beta-propeller architecture in glycoside hydrolase families 32, 43, 62, and 68.
  Proteins, 54, 424-432.  
12974389 E.Tiralongo, I.Martensen, J.Grötzinger, J.Tiralongo, and R.Schauer (2003).
Trans-sialidase-like sequences from Trypanosoma congolense conserve most of the critical active site residues found in other trans-sialidases.
  Biol Chem, 384, 1203-1213.  
12419220 A.Buschiazzo, M.F.Amaya, M.L.Cremona, A.C.Frasch, and P.M.Alzari (2002).
The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis.
  Mol Cell, 10, 757-768.
PDB codes: 1mr5 1ms0 1ms1 1ms3 1ms4 1ms5 1ms8 1ms9
12237289 A.R.Todeschini, M.F.Girard, J.M.Wieruszeski, M.P.Nunes, G.A.DosReis, L.Mendonca-Previato, and J.O.Previato (2002).
trans-Sialidase from Trypanosoma cruzi binds host T-lymphocytes in a lectin manner.
  J Biol Chem, 277, 45962-45968.  
  12197116 A.Saldaña, R.A.Harris, A.Orn, C.Monroy, E.Ortega-Barria, and O.E.Sousa (2002).
Antigenic significance of a Trypanosoma rangeli sialidase.
  J Parasitol, 88, 697-701.  
  12088651 E.Vimr, and C.Lichtensteiger (2002).
To sialylate, or not to sialylate: that is the question.
  Trends Microbiol, 10, 254-257.  
12438397 F.Agüero, V.Campo, L.Cremona, A.Jäger, J.M.Di Noia, P.Overath, D.O.Sánchez, and A.C.Frasch (2002).
Gene discovery in the freshwater fish parasite Trypanosoma carassii: identification of trans-sialidase-like and mucin-like genes.
  Infect Immun, 70, 7140-7144.  
12071958 G.Montagna, M.L.Cremona, G.Paris, M.F.Amaya, A.Buschiazzo, P.M.Alzari, and A.C.Frasch (2002).
The trans-sialidase from the african trypanosome Trypanosoma brucei.
  Eur J Biochem, 269, 2941-2950.  
  12429084 P.M.Colman, and B.J.Smith (2002).
The trypanosomal trans-sialidase: two catalytic functions associated with one catalytic site.
  Structure, 10, 1466-1468.  
11206445 J.A.Harrison, K.P.Kartha, W.B.Turnbull, S.L.Scheuerl, J.H.Naismith, S.Schenkman, and R.A.Field (2001).
Hydrolase and sialyltransferase activities of trypanosoma cruzi trans-sialidase towards NeuAc-alpha-2,3-gal-Gal-beta-O-PNP.
  Bioorg Med Chem Lett, 11, 141-144.  
11179365 T.A.Pitcovsky, J.Mucci, P.Alvarez, M.S.Leguizamón, O.Burrone, P.M.Alzari, and O.Campetella (2001).
Epitope mapping of trans-sialidase from Trypanosoma cruzi reveals the presence of several cross-reactive determinants.
  Infect Immun, 69, 1869-1875.  
11133093 J.C.Wilson, M.J.Kiefel, S.Albouz-Abo, and M.von Itzstein (2000).
Preliminary 1H NMR investigation of sialic acid transfer by the trans-sialidase from Trypanosoma cruzi.
  Bioorg Med Chem Lett, 10, 2791-2794.  
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.