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PDBsum entry 2xr5
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Sugar binding protein
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PDB id
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2xr5
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References listed in PDB file
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Key reference
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Title
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Structure of a glycomimetic ligand in the carbohydrate recognition domain of c-Type lectin dc-Sign. Structural requirements for selectivity and ligand design.
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Authors
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M.Thépaut,
C.Guzzi,
I.Sutkeviciute,
S.Sattin,
R.Ribeiro-Viana,
N.Varga,
E.Chabrol,
J.Rojo,
A.Bernardi,
J.Angulo,
P.M.Nieto,
F.Fieschi.
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Ref.
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J Am Chem Soc, 2013,
135,
2518-2529.
[DOI no: ]
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PubMed id
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Abstract
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In genital mucosa, different fates are described for HIV according to the
subtype of dendritic cells (DCs) involved in its recognition. This notably
depends on the C-type lectin receptor, langerin or DC-SIGN, involved in gp120
interaction. Langerin blocks HIV transmission by its internalization in specific
organelles of Langerhans cells. On the contrary, DC-SIGN enhances HIV
trans-infection of T lymphocytes. Thus, approaches aiming to inhibit DC-SIGN,
without blocking langerin, represent attractive anti-HIV strategies. We
previously demonstrated that dendrons bearing multiple copies of glycomimetic
compounds were able to block DC-SIGN-dependent HIV infection in cervical explant
models. Optimization of such ligand requires detailed characterization of its
binding mode. In the present work, we determined the first high-resolution
structure of a glycomimetic/DC-SIGN complex by X-ray crystallography. This
glycomimetic, pseudo-1,2-mannobioside, shares shape and conformational
properties with ManĪ±1-2Man, its natural counterpart. However, it uses the
binding epitope previously described for Lewis X, a ligand specific for DC-SIGN
among the C-type lectin family. Thus, selectivity gain for DC-SIGN versus
langerin is observed with pseudo-1,2-mannobioside as shown by surface plasmon
resonance analysis. In parallel, ligand binding was also analyzed by TR-NOESY
and STD NMR experiments, combined with the CORCEMA-ST protocol. These studies
demonstrate that the complex, defined by X-ray crystallography, represents the
unique binding mode of this ligand as opposed to the several binding
orientations described for the natural ligand. This exclusive binding mode and
its selective interaction properties position this glycomimetic as a good lead
compound for rational improvement based on a structurally driven approach.
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