Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin

Autores
Zhang, Hengxi; Modenutti, Carlos Pablo; Nekkanti, Yelha Phani Kumar; Denis, Maxime; Bermejo, Iris A.; Lefèbre, Jonathan; Che, Kateryna; Kim, Dongyoon; Kagelmacher, Marten; Kurzbach, Dennis; Nazaré, Marc; Rademacher, Christoph
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Langerin is a mammalian C-type lectin expressed on Langerhans cells in the skin. As an innate immune cell receptor, Langerin is involved in coordinating innate and adaptive immune responses against various incoming threats. We have previously reported a series of thiazolopyrimidines as murine Langerin ligands. Prompted by the observation that its human homologue exhibits different binding specificities for these small molecules, we report here our investigations to define their exact binding site. By using structural comparison and molecular dynamics simulations, we showed that the nonconserved short loops have a high degree of conformational flexibility between the human and murine homologues. Sequence analysis and mutational studies indicated that a pair of residues are essential for the recognition of the thiazolopyrimidines. Taking solvent paramagnetic relaxation enhancement NMR studies together with a series of peptides occupying the same site, we could define the cleft between the short and long loops as the allosteric binding site for these aromatic heterocycles.
Fil: Zhang, Hengxi. Vienna University of Technology; Austria
Fil: Modenutti, Carlos Pablo. 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: Nekkanti, Yelha Phani Kumar. Berlin Institute of Health; Alemania
Fil: Denis, Maxime. Vienna University of Technology; Austria
Fil: Bermejo, Iris A.. Vienna University of Technology; Austria
Fil: Lefèbre, Jonathan. Vienna University of Technology; Austria
Fil: Che, Kateryna. Vienna University of Technology; Austria
Fil: Kim, Dongyoon. Vienna University of Technology; Austria
Fil: Kagelmacher, Marten. Freie Universität Berlin; Alemania
Fil: Kurzbach, Dennis. Vienna University of Technology; Austria
Fil: Nazaré, Marc. Vienna University of Technology; Austria
Fil: Rademacher, Christoph. Vienna University of Technology; Austria
Materia
C-type lectin
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:11336/267772
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/267772
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin LangerinZhang, HengxiModenutti, Carlos PabloNekkanti, Yelha Phani KumarDenis, MaximeBermejo, Iris A.Lefèbre, JonathanChe, KaterynaKim, DongyoonKagelmacher, MartenKurzbach, DennisNazaré, MarcRademacher, ChristophC-type lectinhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Langerin is a mammalian C-type lectin expressed on Langerhans cells in the skin. As an innate immune cell receptor, Langerin is involved in coordinating innate and adaptive immune responses against various incoming threats. We have previously reported a series of thiazolopyrimidines as murine Langerin ligands. Prompted by the observation that its human homologue exhibits different binding specificities for these small molecules, we report here our investigations to define their exact binding site. By using structural comparison and molecular dynamics simulations, we showed that the nonconserved short loops have a high degree of conformational flexibility between the human and murine homologues. Sequence analysis and mutational studies indicated that a pair of residues are essential for the recognition of the thiazolopyrimidines. Taking solvent paramagnetic relaxation enhancement NMR studies together with a series of peptides occupying the same site, we could define the cleft between the short and long loops as the allosteric binding site for these aromatic heterocycles.Fil: Zhang, Hengxi. Vienna University of Technology; AustriaFil: Modenutti, Carlos Pablo. 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: Nekkanti, Yelha Phani Kumar. Berlin Institute of Health; AlemaniaFil: Denis, Maxime. Vienna University of Technology; AustriaFil: Bermejo, Iris A.. Vienna University of Technology; AustriaFil: Lefèbre, Jonathan. Vienna University of Technology; AustriaFil: Che, Kateryna. Vienna University of Technology; AustriaFil: Kim, Dongyoon. Vienna University of Technology; AustriaFil: Kagelmacher, Marten. Freie Universität Berlin; AlemaniaFil: Kurzbach, Dennis. Vienna University of Technology; AustriaFil: Nazaré, Marc. Vienna University of Technology; AustriaFil: Rademacher, Christoph. Vienna University of Technology; AustriaAmerican Chemical Society2022-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/267772Zhang, Hengxi; Modenutti, Carlos Pablo; Nekkanti, Yelha Phani Kumar; Denis, Maxime; Bermejo, Iris A.; et al.; Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin; American Chemical Society; ACS Chemical Biology; 17; 10; 9-2022; 2728-27331554-8929CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.2c00626info:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.2c00626info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:04:11Zoai:ri.conicet.gov.ar:11336/267772instacron: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 11:04:11.618CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
title Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
spellingShingle Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
Zhang, Hengxi
C-type lectin
title_short Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
title_full Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
title_fullStr Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
title_full_unstemmed Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
title_sort Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin
dc.creator.none.fl_str_mv Zhang, Hengxi
Modenutti, Carlos Pablo
Nekkanti, Yelha Phani Kumar
Denis, Maxime
Bermejo, Iris A.
Lefèbre, Jonathan
Che, Kateryna
Kim, Dongyoon
Kagelmacher, Marten
Kurzbach, Dennis
Nazaré, Marc
Rademacher, Christoph
author Zhang, Hengxi
author_facet Zhang, Hengxi
Modenutti, Carlos Pablo
Nekkanti, Yelha Phani Kumar
Denis, Maxime
Bermejo, Iris A.
Lefèbre, Jonathan
Che, Kateryna
Kim, Dongyoon
Kagelmacher, Marten
Kurzbach, Dennis
Nazaré, Marc
Rademacher, Christoph
author_role author
author2 Modenutti, Carlos Pablo
Nekkanti, Yelha Phani Kumar
Denis, Maxime
Bermejo, Iris A.
Lefèbre, Jonathan
Che, Kateryna
Kim, Dongyoon
Kagelmacher, Marten
Kurzbach, Dennis
Nazaré, Marc
Rademacher, Christoph
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv C-type lectin
topic C-type lectin
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Langerin is a mammalian C-type lectin expressed on Langerhans cells in the skin. As an innate immune cell receptor, Langerin is involved in coordinating innate and adaptive immune responses against various incoming threats. We have previously reported a series of thiazolopyrimidines as murine Langerin ligands. Prompted by the observation that its human homologue exhibits different binding specificities for these small molecules, we report here our investigations to define their exact binding site. By using structural comparison and molecular dynamics simulations, we showed that the nonconserved short loops have a high degree of conformational flexibility between the human and murine homologues. Sequence analysis and mutational studies indicated that a pair of residues are essential for the recognition of the thiazolopyrimidines. Taking solvent paramagnetic relaxation enhancement NMR studies together with a series of peptides occupying the same site, we could define the cleft between the short and long loops as the allosteric binding site for these aromatic heterocycles.
Fil: Zhang, Hengxi. Vienna University of Technology; Austria
Fil: Modenutti, Carlos Pablo. 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: Nekkanti, Yelha Phani Kumar. Berlin Institute of Health; Alemania
Fil: Denis, Maxime. Vienna University of Technology; Austria
Fil: Bermejo, Iris A.. Vienna University of Technology; Austria
Fil: Lefèbre, Jonathan. Vienna University of Technology; Austria
Fil: Che, Kateryna. Vienna University of Technology; Austria
Fil: Kim, Dongyoon. Vienna University of Technology; Austria
Fil: Kagelmacher, Marten. Freie Universität Berlin; Alemania
Fil: Kurzbach, Dennis. Vienna University of Technology; Austria
Fil: Nazaré, Marc. Vienna University of Technology; Austria
Fil: Rademacher, Christoph. Vienna University of Technology; Austria
description Langerin is a mammalian C-type lectin expressed on Langerhans cells in the skin. As an innate immune cell receptor, Langerin is involved in coordinating innate and adaptive immune responses against various incoming threats. We have previously reported a series of thiazolopyrimidines as murine Langerin ligands. Prompted by the observation that its human homologue exhibits different binding specificities for these small molecules, we report here our investigations to define their exact binding site. By using structural comparison and molecular dynamics simulations, we showed that the nonconserved short loops have a high degree of conformational flexibility between the human and murine homologues. Sequence analysis and mutational studies indicated that a pair of residues are essential for the recognition of the thiazolopyrimidines. Taking solvent paramagnetic relaxation enhancement NMR studies together with a series of peptides occupying the same site, we could define the cleft between the short and long loops as the allosteric binding site for these aromatic heterocycles.
publishDate 2022
dc.date.none.fl_str_mv 2022-09
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/11336/267772
Zhang, Hengxi; Modenutti, Carlos Pablo; Nekkanti, Yelha Phani Kumar; Denis, Maxime; Bermejo, Iris A.; et al.; Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin; American Chemical Society; ACS Chemical Biology; 17; 10; 9-2022; 2728-2733
1554-8929
CONICET Digital
CONICET
url http://hdl.handle.net/11336/267772
identifier_str_mv Zhang, Hengxi; Modenutti, Carlos Pablo; Nekkanti, Yelha Phani Kumar; Denis, Maxime; Bermejo, Iris A.; et al.; Identification of the Allosteric Binding Site for Thiazolopyrimidine on the C-Type Lectin Langerin; American Chemical Society; ACS Chemical Biology; 17; 10; 9-2022; 2728-2733
1554-8929
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.2c00626
info:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.2c00626
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
_version_ 1846781292928040960
score 12.982451

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