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

Wawrzinek, Robert; Wamhoff, Eike-Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; Domeniconi, Gary; Schulze, Jessica; Fuchsberger, Felix F.; Zhang, Heng-Xi; 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

doi:10.1021/jacs.1c07235

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

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Wawrzinek, Robert
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons144973

Wamhoff, Eike-Christian
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

Lefebre, Jonathan
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons238083

Rentzsch, Mareike
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons141943

Schulze, Jessica
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons222832

Fuchsberger, Felix F.
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons220662

Zhang, Heng-Xi
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

Schnirch, Lennart
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons239941

Bräutigam, Maria
Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons209402

Guberman, Mónica
Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons121849

Seeberger, Peter H.
Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

/persons/resource/persons121753

Rademacher, Christoph
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0009-7A09-5

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.