Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering.

Abstract : DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLR) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand 2.
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Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2016, 14 (1), pp.335-344
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http://hal.univ-grenoble-alpes.fr/hal-01235344
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Soumis le : lundi 30 novembre 2015 - 09:43:45
Dernière modification le : jeudi 11 janvier 2018 - 06:15:24

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  • HAL Id : hal-01235344, version 1
  • PUBMED : 26611567

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C Guzzi, P Alfarano, Ieva Sutkeviciute, S Sattin, R Ribeiro-Viana, et al.. Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering.. Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2016, 14 (1), pp.335-344. 〈hal-01235344〉

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