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PDBsum entry 1ms3
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The crystal structure and mode of action of trans-Sialidase, A key enzyme in trypanosoma cruzi pathogenesis.
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Authors
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A.Buschiazzo,
M.F.Amaya,
M.L.Cremona,
A.C.Frasch,
P.M.Alzari.
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Ref.
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Mol Cell, 2002,
10,
757-768.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2002,
10,
757-768)
copyright 2002.
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