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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/210230
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:24:51Zoai: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:34982025-09-29 10:24:51.309CONICET 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 |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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13.070432 |