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A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN.
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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ID |
4635456 |
Author(s) |
Wawrzinek, Robert; Wamhoff, Eike-Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; Domeniconi, Gary; Schulze, Jessica; Fuchsberger, Felix F; Zhang, Hengxi; Modenutti, Carlos; Schnirch, Lennart; Marti, Marcelo A; Schwardt, Oliver; Bräutigam, Maria; Guberman, Mónica; Hauck, Dirk; Seeberger, Peter H; Seitz, Oliver; Titz, Alexander; Ernst, Beat; Rademacher, Christoph |
Author(s) at UniBasel |
Ernst, Beat Schwardt, Oliver
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Year |
2021 |
Title |
A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN. |
Journal |
Journal of the American Chemical Society |
Volume |
143 |
Number |
45 |
Pages / Article-Number |
18977-18988 |
Abstract |
Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN; +; but not for Langerin; +; cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN's carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general. |
ISSN/ISBN |
1520-5126 |
Full Text on edoc |
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Digital Object Identifier DOI |
10.1021/jacs.1c07235 |
PubMed ID |
http://www.ncbi.nlm.nih.gov/pubmed/34748320 |
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20/04/2024
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