Titel
A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
Autor*in
Robert Wawrzinek
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces
Eike-Christian Wamhoff
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces
Jonathan Lefebre
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces
... show all
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.
Stichwort
CarbohydratesChemical biologyLigandsTargetingVesicles
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Journal of the American Chemical Society
Band
143
Ausgabe
45
ISSN
0002-7863
Erscheinungsdatum
2021
Seitenanfang
18977
Seitenende
18988
Publication
American Chemical Society (ACS)
Erscheinungsdatum
2021
Zugänglichkeit
Rechte
Rechteangabe
© 2021 The Authors
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