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  A remote secondary binding pocket promotes heteromultivalent targeting of DC-SIGN

Wawrzinek, R., Wamhoff, E.-C., Lefebre, J., Rentzsch, M., Bachem, G., Domeniconi, G., et al. (2021). A remote secondary binding pocket promotes heteromultivalent targeting of DC-SIGN. Journal of the American Chemical Society, 143(45), 18977-18988. doi:10.1021/jacs.1c07235.

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Wawrzinek, Robert1, Author              
Wamhoff, Eike-Christian1, Author              
Lefebre, Jonathan1, Author
Rentzsch, Mareike1, Author              
Bachem, Gunnar, Author
Domeniconi, Gary, Author
Schulze, Jessica1, Author              
Fuchsberger, Felix F.1, Author              
Zhang, Heng-Xi1, Author              
Modenutti, Carlos, Author
Schnirch, Lennart1, Author
Marti, Marcelo A., Author
Schwardt, Oliver, Author
Bräutigam, Maria2, Author              
Guberman, Mónica2, Author              
Hauck, Dirk, Author
Seeberger, Peter H.2, Author              
Seitz, Oliver, Author
Titz, Alexander, Author
Ernst, Beat, Author
Rademacher, Christoph1, Author               more..
Affiliations:
1Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863300              
2Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863308              

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 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.

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Language(s): eng - English
 Dates: 2021-11-082021
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: DOI: 10.1021/jacs.1c07235
BibTex Citekey: doi:10.1021/jacs.1c07235
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Title: Journal of the American Chemical Society
  Other : JACS
  Abbreviation : J. Am. Chem. Soc.
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 143 (45) Sequence Number: - Start / End Page: 18977 - 18988 Identifier: ISSN: 0002-7863