A solution NMR study of the interactions of oligomannosides and the anti-HIV-1 2G12 antibody reveals distinct binding modes for branched ligands

Enríquez-Navas, Pedro M, Marradi, Marco, Padro, Daniel, Angulo, Jesús and Penadés, Soledad (2011) A solution NMR study of the interactions of oligomannosides and the anti-HIV-1 2G12 antibody reveals distinct binding modes for branched ligands. Chemistry - A European Journal, 17 (5). pp. 1547-1560. ISSN 0947-6539

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Abstract

The structural and affinity details of the interactions of synthetic oligomannosides, linear (di-, tri-, and tetra-) and branched (penta- and hepta-), with the broadly neutralizing anti-HIV-1 antibody 2G12 (HIV=human immunodeficiency virus) have been investigated in solution by using ligand-based NMR techniques, specifically saturation transfer difference (STD) NMR spectroscopy and transferred NOE experiments. Linear oligomannosides show similar binding modes to the antibody, with the nonreducing terminal disaccharide Mana(1?2)Man (Man=mannose) making the closest protein/ligand contacts in the bound state. In contrast, the branched pentamannoside shows two alternate binding modes, involving both ligand arms (D2- and D3-like), a dual binding description of the molecular recognition of this ligand by 2G12 in solution that differs from the single binding mode deduced from X-ray studies. On the contrary, the antibody shows an unexpected selectivity for one arm (D1-like) of the other branched ligand (heptamannoside). This result explains the previously reported lack of affinity enhancement relative to that of the D1-like tetramannoside. Single-ligand STD NMR titration experiments revealed noticeable differences in binding affinities among the linear and branched ligands in solution, with the latter showing decreased affinity. Among the analyzed series of ligands, the strongest 2G12 binders were the linear tri- and tetramannosides because both show similar affinity for the antibody. These results demonstrate that NMR spectroscopic techniques can deliver abundant structural, dynamics, and affinity information for the characterization of oligomannose-2G12 binding in solution, thus complementing, and, as in the case of the pentamannoside, extending, the structural view from X-ray crystallography. This information is of key importance for the development of multivalent synthetic gp120 high-mannose glycoconjugate mimics in the context of vaccine development.

Item Type: Article
Additional Information: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Uncontrolled Keywords: molecular structure,hiv antibodies,humans,oligosaccharides, branched-chain,amino acid sequence,glycoconjugates,hiv-1,magnetic resonance spectroscopy,antibodies, monoclonal,hiv envelope protein gp120,oligosaccharides,carbohydrate sequence,molecular sequence data,crystallography, x-ray,binding sites, antibody,ligands
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 21 Oct 2013 12:46
Last Modified: 21 Apr 2020 22:01
URI: https://ueaeprints.uea.ac.uk/id/eprint/43763
DOI: 10.1002/chem.201002519

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