A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

Autores
Wawrzinek, Robert; Wamhoff, Eike Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; Domeniconi, Gary; Schulze, Jessica; Fuchsberger, Felix F.; Zhang, Hengxi; Modenutti, Carlos Pablo; Schnirch, Lennart; Marti, Marcelo Adrian; Schwardt, Oliver; Bräutigam, Maria; Guberman, Mónica; Hauck, Dirk; Seeberger, Peter H.; Seitz, Oliver; Titz, Alexander; Ernst, Beat; Rademacher, Christoph
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Wawrzinek, Robert. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Wamhoff, Eike Christian. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Lefebre, Jonathan. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Rentzsch, Mareike. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Bachem, Gunnar. Humboldt-Universität zu Berlin; Alemania
Fil: Domeniconi, Gary. Humboldt-Universität zu Berlin; Alemania
Fil: Schulze, Jessica. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Fuchsberger, Felix F.. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Zhang, Hengxi. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Modenutti, Carlos Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Schnirch, Lennart. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Schwardt, Oliver. Universidad de Basilea; Suiza
Fil: Bräutigam, Maria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Guberman, Mónica. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Hauck, Dirk. Helmholtz Gemeinschaft; Alemania
Fil: Seeberger, Peter H.. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Seitz, Oliver. Humboldt-Universität zu Berlin; Alemania
Fil: Titz, Alexander. Universitat Saarland; Alemania. Helmholtz Gemeinschaft; Alemania
Fil: Ernst, Beat. Universidad de Basilea; Suiza
Fil: Rademacher, Christoph. Universidad de Viena; Austria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Materia
Docking
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/210230
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/210230
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGNWawrzinek, RobertWamhoff, Eike ChristianLefebre, JonathanRentzsch, MareikeBachem, GunnarDomeniconi, GarySchulze, JessicaFuchsberger, Felix F.Zhang, HengxiModenutti, Carlos PabloSchnirch, LennartMarti, Marcelo AdrianSchwardt, OliverBräutigam, MariaGuberman, MónicaHauck, DirkSeeberger, Peter H.Seitz, OliverTitz, AlexanderErnst, BeatRademacher, ChristophDockinghttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Dendritic 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.Fil: Wawrzinek, Robert. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Wamhoff, Eike Christian. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; AlemaniaFil: Lefebre, Jonathan. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; AlemaniaFil: Rentzsch, Mareike. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Bachem, Gunnar. Humboldt-Universität zu Berlin; AlemaniaFil: Domeniconi, Gary. Humboldt-Universität zu Berlin; AlemaniaFil: Schulze, Jessica. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Fuchsberger, Felix F.. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Zhang, Hengxi. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Modenutti, Carlos Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Schnirch, Lennart. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; AlemaniaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Schwardt, Oliver. Universidad de Basilea; SuizaFil: Bräutigam, Maria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Guberman, Mónica. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; AlemaniaFil: Hauck, Dirk. Helmholtz Gemeinschaft; AlemaniaFil: Seeberger, Peter H.. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; AlemaniaFil: Seitz, Oliver. Humboldt-Universität zu Berlin; AlemaniaFil: Titz, Alexander. Universitat Saarland; Alemania. Helmholtz Gemeinschaft; AlemaniaFil: Ernst, Beat. Universidad de Basilea; SuizaFil: Rademacher, Christoph. Universidad de Viena; Austria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; AlemaniaAmerican Chemical Society2021-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/210230Wawrzinek, Robert; Wamhoff, Eike Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; et al.; A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN; American Chemical Society; Journal of the American Chemical Society; 143; 45; 11-2021; 18977-189880002-7863CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/jacs.1c07235info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jacs.1c07235info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:57:32Zoai:ri.conicet.gov.ar:11336/210230instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:57:33.17CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
title A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
spellingShingle A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
Wawrzinek, Robert
Docking
title_short A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
title_full A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
title_fullStr A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
title_full_unstemmed A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
title_sort A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN
dc.creator.none.fl_str_mv Wawrzinek, Robert
Wamhoff, Eike Christian
Lefebre, Jonathan
Rentzsch, Mareike
Bachem, Gunnar
Domeniconi, Gary
Schulze, Jessica
Fuchsberger, Felix F.
Zhang, Hengxi
Modenutti, Carlos Pablo
Schnirch, Lennart
Marti, Marcelo Adrian
Schwardt, Oliver
Bräutigam, Maria
Guberman, Mónica
Hauck, Dirk
Seeberger, Peter H.
Seitz, Oliver
Titz, Alexander
Ernst, Beat
Rademacher, Christoph
author Wawrzinek, Robert
author_facet Wawrzinek, Robert
Wamhoff, Eike Christian
Lefebre, Jonathan
Rentzsch, Mareike
Bachem, Gunnar
Domeniconi, Gary
Schulze, Jessica
Fuchsberger, Felix F.
Zhang, Hengxi
Modenutti, Carlos Pablo
Schnirch, Lennart
Marti, Marcelo Adrian
Schwardt, Oliver
Bräutigam, Maria
Guberman, Mónica
Hauck, Dirk
Seeberger, Peter H.
Seitz, Oliver
Titz, Alexander
Ernst, Beat
Rademacher, Christoph
author_role author
author2 Wamhoff, Eike Christian
Lefebre, Jonathan
Rentzsch, Mareike
Bachem, Gunnar
Domeniconi, Gary
Schulze, Jessica
Fuchsberger, Felix F.
Zhang, Hengxi
Modenutti, Carlos Pablo
Schnirch, Lennart
Marti, Marcelo Adrian
Schwardt, Oliver
Bräutigam, Maria
Guberman, Mónica
Hauck, Dirk
Seeberger, Peter H.
Seitz, Oliver
Titz, Alexander
Ernst, Beat
Rademacher, Christoph
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Docking
topic Docking
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Wawrzinek, Robert. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Wamhoff, Eike Christian. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Lefebre, Jonathan. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Rentzsch, Mareike. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Bachem, Gunnar. Humboldt-Universität zu Berlin; Alemania
Fil: Domeniconi, Gary. Humboldt-Universität zu Berlin; Alemania
Fil: Schulze, Jessica. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Fuchsberger, Felix F.. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Zhang, Hengxi. Freie Universität Berlin; Alemania. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Modenutti, Carlos Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Schnirch, Lennart. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Schwardt, Oliver. Universidad de Basilea; Suiza
Fil: Bräutigam, Maria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Guberman, Mónica. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania
Fil: Hauck, Dirk. Helmholtz Gemeinschaft; Alemania
Fil: Seeberger, Peter H.. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
Fil: Seitz, Oliver. Humboldt-Universität zu Berlin; Alemania
Fil: Titz, Alexander. Universitat Saarland; Alemania. Helmholtz Gemeinschaft; Alemania
Fil: Ernst, Beat. Universidad de Basilea; Suiza
Fil: Rademacher, Christoph. Universidad de Viena; Austria. Max-planck-institut Für Kolloid- Und Grenzflächenforschung; Alemania. Freie Universität Berlin; Alemania
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/210230
Wawrzinek, Robert; Wamhoff, Eike Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; et al.; A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN; American Chemical Society; Journal of the American Chemical Society; 143; 45; 11-2021; 18977-18988
0002-7863
CONICET Digital
CONICET
url http://hdl.handle.net/11336/210230
identifier_str_mv Wawrzinek, Robert; Wamhoff, Eike Christian; Lefebre, Jonathan; Rentzsch, Mareike; Bachem, Gunnar; et al.; A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN; American Chemical Society; Journal of the American Chemical Society; 143; 45; 11-2021; 18977-18988
0002-7863
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/jacs.1c07235
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jacs.1c07235
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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