PDBsum entry 1ms3

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protein Protein-protein interface(s) links
Hydrolase PDB id
Jmol PyMol
Protein chains
623 a.a. *
Waters ×1152
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Monoclinic form of trypanosoma cruzi trans-sialidase
Structure: Trans-sialidase. Chain: a, b. Fragment: enzymatic globular core. Engineered: yes. Mutation: yes
Source: Trypanosoma cruzi. Organism_taxid: 5693. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.65Å     R-factor:   0.164     R-free:   0.192
Authors: A.Buschiazzo,M.F.Amaya,M.L.Cremona,A.C.Frasch,P.M.Alzari
Key ref:
A.Buschiazzo et al. (2002). The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis. Mol Cell, 10, 757-768. PubMed id: 12419220 DOI: 10.1016/S1097-2765(02)00680-9
19-Sep-02     Release date:   25-Mar-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q26966  (Q26966_TRYCR) -  Trans-sialidase
642 a.a.
623 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 11 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - 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     pathogenesis   1 term 
  Biochemical function     exo-alpha-sialidase activity     1 term  


DOI no: 10.1016/S1097-2765(02)00680-9 Mol Cell 10:757-768 (2002)
PubMed id: 12419220  
The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis.
A.Buschiazzo, M.F.Amaya, M.L.Cremona, A.C.Frasch, P.M.Alzari.
Trans-sialidases (TS) are GPI-anchored surface enzymes expressed in specific developmental stages of trypanosome parasites like Trypanosoma cruzi, the etiologic agent of Chagas disease, and T. brucei, the causative agent of sleeping sickness. TS catalyzes the transfer of sialic acid residues from host to parasite glycoconjugates through a transglycosidase reaction that appears to be critical for T. cruzi survival and cell invasion capability. We report here the structure of the T. cruzi trans-sialidase, alone and in complex with sugar ligands. Sialic acid binding is shown to trigger a conformational switch that modulates the affinity for the acceptor substrate and concomitantly creates the conditions for efficient transglycosylation. The structure provides a framework for the structure-based design of novel inhibitors with potential therapeutic applications.
  Selected figure(s)  
Figure 4.
Figure 4. Lactose Binding to TcTS(A) Complete BIAcore sensorgrams showing the interaction between the inactive mutant Asp59Asn and sialic acid (continuous line). Lactose (10 mM) was injected after equilibrating the protein in the presence (continuous line) or absence (dashed line) of sialic acid.(b) Detailed view of the interaction between TcTS and lactose, demonstrating that the acceptor substrate only binds to TcTS when sialic acid is present.
Figure 5.
Figure 5. TcTS-Lactose Interactions(A) Electron density (2Fo-Fc) map, contoured at 1 σ, of the lactose binding site in the triclinic crystal form. The loop containing Gly145/Gly146 from a neighbor molecule in the crystal is also shown.(B) Electron density (2Fo-Fc) map, contoured at 1 σ, showing the lactose and DANA molecules in the ternary complex.(C) Schematic diagram showing protein-carbohydrate hydrogen bonding interactions.(D) Stacking interactions of the lactose moiety with the aromatic rings of Trp312 and Tyr119 in the ternary complex.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2002, 10, 757-768) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21283717 H.Bora, S.Garg, P.Sen, D.Kumar, P.Kaur, R.H.Khan, and Y.D.Sharma (2011).
Plasmodium vivax Tryptophan-Rich Antigen PvTRAg33.5 Contains Alpha Helical Structure and Multidomain Architecture.
  PLoS One, 6, e16294.  
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.  
21040619 R.R.Tonelli, A.C.Torrecilhas, J.F.Jacysyn, M.A.Juliano, W.Colli, and M.J.Alves (2011).
In vivo infection by Trypanosoma cruzi: the conserved FLY domain of the gp85/trans-sialidase family potentiates host infection.
  Parasitology, 138, 481-492.  
21240549 T.Lieke, D.Gröbe, V.Blanchard, D.Grunow, R.Tauber, M.Zimmermann-Kordmann, T.Jacobs, and W.Reutter (2011).
Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines.
  Glycoconj J, 28, 31-37.  
20441732 F.L.Mitchell, S.M.Miles, J.Neres, E.V.Bichenkova, and R.A.Bryce (2010).
Tryptophan as a molecular shovel in the glycosyl transfer activity of Trypanosoma cruzi trans-sialidase.
  Biophys J, 98, L38-L40.  
19880425 J.Cheng, S.Huang, H.Yu, Y.Li, K.Lau, and X.Chen (2010).
Trans-sialidase activity of Photobacterium damsela alpha2,6-sialyltransferase and its application in the synthesis of sialosides.
  Glycobiology, 20, 260-268.  
20645127 M.E.Giorgi, L.Ratier, R.Agusti, A.C.Frasch, and Lederkremer (2010).
Synthesis of PEGylated lactose analogs for inhibition studies on T.cruzi trans-sialidase.
  Glycoconj J, 27, 549-559.  
20375068 P.A.Sartor, R.Agusti, M.S.Leguizamón, O.Campetella, and Lederkremer (2010).
Continuous nonradioactive method for screening trypanosomal trans-sialidase activity and its inhibitors.
  Glycobiology, 20, 982-990.  
20466651 S.T.Carvalho, M.Sola-Penna, I.A.Oliveira, S.Pita, A.S.Gonçalves, B.C.Neves, F.R.Sousa, L.Freire-de-Lima, M.Kurogochi, H.Hinou, S.Nishimura, L.Mendonça-Previato, J.O.Previato, and A.R.Todeschini (2010).
A new class of mechanism-based inhibitors for Trypanosoma cruzi trans-sialidase and their influence on parasite virulence.
  Glycobiology, 20, 1034-1045.  
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.  
19283409 F.Villalta, J.Scharfstein, A.W.Ashton, K.M.Tyler, F.Guan, S.Mukherjee, M.F.Lima, S.Alvarez, L.M.Weiss, H.Huang, F.S.Machado, and H.B.Tanowitz (2009).
Perspectives on the Trypanosoma cruzi-host cell receptor interactions.
  Parasitol Res, 104, 1251-1260.  
19552697 H.Erdmann, C.Steeg, F.Koch-Nolte, B.Fleischer, and T.Jacobs (2009).
Sialylated ligands on pathogenic Trypanosoma cruzi interact with Siglec-E (sialic acid-binding Ig-like lectin-E).
  Cell Microbiol, 11, 1600-1611.  
19780074 J.H.Kim, H.W.Ryu, J.H.Shim, K.H.Park, and S.G.Withers (2009).
Development of new and selective Trypanosoma cruzi trans-sialidase inhibitors from sulfonamide chalcones and their derivatives.
  Chembiochem, 10, 2475-2479.  
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.  
19750531 S.A.Allman, H.H.Jensen, B.Vijayakrishnan, J.A.Garnett, E.Leon, Y.Liu, D.C.Anthony, N.R.Sibson, T.Feizi, S.Matthews, and B.G.Davis (2009).
Potent fluoro-oligosaccharide probes of adhesion in Toxoplasmosis.
  Chembiochem, 10, 2522-2529.  
19687228 S.Uchiyama, A.F.Carlin, A.Khosravi, S.Weiman, A.Banerjee, D.Quach, G.Hightower, T.J.Mitchell, K.S.Doran, and V.Nizet (2009).
The surface-anchored NanA protein promotes pneumococcal brain endothelial cell invasion.
  J Exp Med, 206, 1845-1852.  
18410251 B.Lu, Z.Petrola, A.O.Luquetti, and M.PereiraPerrin (2008).
Auto-antibodies to receptor tyrosine kinases TrkA, TrkB and TrkC in patients with chronic Chagas' disease.
  Scand J Immunol, 67, 603-609.  
18508467 F.Villalta, M.N.Madison, Y.Y.Kleshchenko, P.N.Nde, and M.F.Lima (2008).
Molecular analysis of early host cell infection by Trypanosoma cruzi.
  Front Biosci, 13, 3714-3734.  
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
16298994 A.G.Watts, P.Oppezzo, S.G.Withers, P.M.Alzari, and A.Buschiazzo (2006).
Structural and kinetic analysis of two covalent sialosyl-enzyme intermediates on Trypanosoma rangeli sialidase.
  J Biol Chem, 281, 4149-4155.
PDB codes: 2a75 2ags 2fhr
16607670 B.Neubacher, S.Scheid, S.Kelm, A.C.Frasch, B.Meyer, and J.Thiem (2006).
Synthesis of Neu5Ac oligosaccharides and analogues by transglycosylation and their binding properties as ligands to MAG.
  Chembiochem, 7, 896-899.  
16489349 C.A.Buscaglia, V.A.Campo, A.C.Frasch, and J.M.Di Noia (2006).
Trypanosoma cruzi surface mucins: host-dependent coat diversity.
  Nat Rev Microbiol, 4, 229-236.  
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.  
16230015 H.Streicher, and H.Busse (2006).
Building a successful structural motif into sialylmimetics-cyclohexenephosphonate monoesters as pseudo-sialosides with promising inhibitory properties.
  Bioorg Med Chem, 14, 1047-1057.  
16819962 J.Mucci, M.G.Risso, M.S.Leguizamón, A.C.Frasch, and O.Campetella (2006).
The trans-sialidase from Trypanosoma cruzi triggers apoptosis by target cell sialylation.
  Cell Microbiol, 8, 1086-1095.  
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.  
  16511237 D.M.Anstrom, L.Colip, B.Moshofsky, E.Hatcher, and S.J.Remington (2005).
Systematic replacement of lysine with glutamine and alanine in Escherichia coli malate synthase G: effect on crystallization.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 1069-1074.  
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
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 code: 2bzd
14634017 A.R.Todeschini, W.B.Dias, M.F.Girard, J.M.Wieruszeski, L.Mendonça-Previato, and J.O.Previato (2004).
Enzymatically inactive trans-sialidase from Trypanosoma cruzi binds sialyl and beta-galactopyranosyl residues in a sequential ordered mechanism.
  J Biol Chem, 279, 5323-5328.  
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 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.  
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.  
12649268 E.Tiralongo, S.Schrader, H.Lange, H.Lemke, J.Tiralongo, and R.Schauer (2003).
Two trans-sialidase forms with different sialic acid transfer and sialidase activities from Trypanosoma congolense.
  J Biol Chem, 278, 23301-23310.  
12878003 L.C.James, and D.S.Tawfik (2003).
Conformational diversity and protein evolution--a 60-year-old hypothesis revisited.
  Trends Biochem Sci, 28, 361-368.  
14732928 R.L.Rich, and D.G.Myszka (2003).
A survey of the year 2002 commercial optical biosensor literature.
  J Mol Recognit, 16, 351-382.  
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.  
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.