[NMR paper] Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.

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Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.

Related Articles Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.

J Biol Chem. 2013 Jun 20;

Authors: Probert F, Whittaker SB, Crispin M, Mitchell DA, Dixon AM

Abstract
The C-type lectin DC-SIGNR (Dendritic Cell-Specific ICAM-3-Grabbing Non-integrin-Related; L-SIGN; CD299) is a promising drug target due to its ability to promote infection and/or within-host survival of several dangerous pathogens (e.g. HIV, SARS) via interactions with their surface glycans. Crystallography has provided excellent insight into the mechanism by which DC-SIGNR interacts with small glycans such as (GlcNAc)2Man3, however direct observation of complexes with larger, physiological oligosaccharides such as Man9GlcNAc2 remains elusive. We have utilised solution-state nuclear magnetic resonance spectroscopy to investigate DC-SIGNR binding and herein report the first backbone assignment of its active, calcium-bound carbohydrate recognition domain (CRD). Direct interactions with the small sugar fragments Man3, Man5 and (GlcNAc)2Man3 were investigated alongside Man9GlcNAc derived from recombinant gp120 (present on the HIV viral envelope), providing the first structural data for DC-SIGNR in complex with a virus-associated ligand, and unique binding modes were observed for each glycan. In particular, our data show that DC-SIGNR has a different binding mode for glycans on the HIV viral envelope compared with the smaller glycans previously observed in the crystalline state. This suggests that using the binding mode of Man9GlcNAc, instead of those of small glycans, may provide a platform for the design of DC-SIGNR inhibitors selective for high-mannose glycans (like those on HIV). 15N relaxation measurements provided the first information on the dynamics of the CRD, demonstrating that it is a highly flexible domain that undergoes ligand-induced conformational and dynamics changes which may explain the ability of DC-SIGNR to accommodate a range of glycans on viral surfaces.


PMID: 23788638 [PubMed - as supplied by publisher]



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