Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition

Autores
Faustino, André F; Guerra, Gabriela M.; Huber, Roland G.; Hollmann, Axel; Domingues, Marco M.; Barbosa, Galuce M.; Enguita, Francisco J.; Bond, Peter J.; Castanho, Miguel A. R. B.; Da Poian, Andrea T. Da Poian; Almeida, Fabio C. L.; Santos, Nuno C.; Martins, Ivo C.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), which is crucial for viral replication. Combining bioinformatics and biophysics, here, we analyzed pep14-23 structure and ability to bind different phospholipids, relating that information with the full-length DENV C. We show that pep14-23 acquires α-helical conformation upon binding to negatively charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV andsimilar Flavivirus infections.
Fil: Faustino, André F. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Guerra, Gabriela M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Huber, Roland G.. Agency for Science, Technology and Research. Bioinformatics Institute; Singapur
Fil: Hollmann, Axel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Domingues, Marco M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Barbosa, Galuce M.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil
Fil: Enguita, Francisco J.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Bond, Peter J.. Agency for Science, Technology and Research. Bioinformatics Institute; Singapur. National University of Singapore. Department of Biological Sciences; Singapur
Fil: Castanho, Miguel A. R. B.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Da Poian, Andrea T. Da Poian. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil
Fil: Almeida, Fabio C. L.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil. Universidade Federal do Rio de Janeiro. Centro Nacional de Ressonancia Magnêtica Nuclear; Brasil
Fil: Santos, Nuno C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Martins, Ivo C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Materia
Dengue
Denv C
Lipid Droplets
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/3826
Acceder
id CONICETDig_f833bc4c173a5e11de4a2f53444d664d
oai_identifier_str oai:ri.conicet.gov.ar:11336/3826
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based InhibitionFaustino, André FGuerra, Gabriela M.Huber, Roland G.Hollmann, AxelDomingues, Marco M.Barbosa, Galuce M.Enguita, Francisco J.Bond, Peter J.Castanho, Miguel A. R. B.Da Poian, Andrea T. Da PoianAlmeida, Fabio C. L.Santos, Nuno C.Martins, Ivo C.DengueDenv CLipid Dropletshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), which is crucial for viral replication. Combining bioinformatics and biophysics, here, we analyzed pep14-23 structure and ability to bind different phospholipids, relating that information with the full-length DENV C. We show that pep14-23 acquires α-helical conformation upon binding to negatively charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV andsimilar Flavivirus infections.Fil: Faustino, André F. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Guerra, Gabriela M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Huber, Roland G.. Agency for Science, Technology and Research. Bioinformatics Institute; SingapurFil: Hollmann, Axel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Domingues, Marco M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Barbosa, Galuce M.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; BrasilFil: Enguita, Francisco J.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Bond, Peter J.. Agency for Science, Technology and Research. Bioinformatics Institute; Singapur. National University of Singapore. Department of Biological Sciences; SingapurFil: Castanho, Miguel A. R. B.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Da Poian, Andrea T. Da Poian. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; BrasilFil: Almeida, Fabio C. L.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil. Universidade Federal do Rio de Janeiro. Centro Nacional de Ressonancia Magnêtica Nuclear; BrasilFil: Santos, Nuno C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalFil: Martins, Ivo C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; PortugalAmerican Chemical Society2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/3826Faustino, André F; Guerra, Gabriela M.; Huber, Roland G.; Hollmann, Axel; Domingues, Marco M.; et al.; Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition; American Chemical Society; Acs Chemical Biology; 10; 2; 2-2015; 517-5261554-8929enginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/cb500640tinfo:eu-repo/semantics/altIdentifier/issn/1554-8929info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/DOI:10.1021/cb500640tinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:10Zoai:ri.conicet.gov.ar:11336/3826instacron: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:34982025-09-03 09:53:10.286CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
title Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
spellingShingle Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
Faustino, André F
Dengue
Denv C
Lipid Droplets
title_short Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
title_full Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
title_fullStr Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
title_full_unstemmed Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
title_sort Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition
dc.creator.none.fl_str_mv Faustino, André F
Guerra, Gabriela M.
Huber, Roland G.
Hollmann, Axel
Domingues, Marco M.
Barbosa, Galuce M.
Enguita, Francisco J.
Bond, Peter J.
Castanho, Miguel A. R. B.
Da Poian, Andrea T. Da Poian
Almeida, Fabio C. L.
Santos, Nuno C.
Martins, Ivo C.
author Faustino, André F
author_facet Faustino, André F
Guerra, Gabriela M.
Huber, Roland G.
Hollmann, Axel
Domingues, Marco M.
Barbosa, Galuce M.
Enguita, Francisco J.
Bond, Peter J.
Castanho, Miguel A. R. B.
Da Poian, Andrea T. Da Poian
Almeida, Fabio C. L.
Santos, Nuno C.
Martins, Ivo C.
author_role author
author2 Guerra, Gabriela M.
Huber, Roland G.
Hollmann, Axel
Domingues, Marco M.
Barbosa, Galuce M.
Enguita, Francisco J.
Bond, Peter J.
Castanho, Miguel A. R. B.
Da Poian, Andrea T. Da Poian
Almeida, Fabio C. L.
Santos, Nuno C.
Martins, Ivo C.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dengue
Denv C
Lipid Droplets
topic Dengue
Denv C
Lipid Droplets
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), which is crucial for viral replication. Combining bioinformatics and biophysics, here, we analyzed pep14-23 structure and ability to bind different phospholipids, relating that information with the full-length DENV C. We show that pep14-23 acquires α-helical conformation upon binding to negatively charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV andsimilar Flavivirus infections.
Fil: Faustino, André F. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Guerra, Gabriela M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Huber, Roland G.. Agency for Science, Technology and Research. Bioinformatics Institute; Singapur
Fil: Hollmann, Axel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Domingues, Marco M.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Barbosa, Galuce M.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil
Fil: Enguita, Francisco J.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Bond, Peter J.. Agency for Science, Technology and Research. Bioinformatics Institute; Singapur. National University of Singapore. Department of Biological Sciences; Singapur
Fil: Castanho, Miguel A. R. B.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Da Poian, Andrea T. Da Poian. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil
Fil: Almeida, Fabio C. L.. Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Medica Leopoldo de Meis; Brasil. Universidade Federal do Rio de Janeiro. Centro Nacional de Ressonancia Magnêtica Nuclear; Brasil
Fil: Santos, Nuno C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
Fil: Martins, Ivo C.. Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular; Portugal
description Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), which is crucial for viral replication. Combining bioinformatics and biophysics, here, we analyzed pep14-23 structure and ability to bind different phospholipids, relating that information with the full-length DENV C. We show that pep14-23 acquires α-helical conformation upon binding to negatively charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV andsimilar Flavivirus infections.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
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/11336/3826
Faustino, André F; Guerra, Gabriela M.; Huber, Roland G.; Hollmann, Axel; Domingues, Marco M.; et al.; Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition; American Chemical Society; Acs Chemical Biology; 10; 2; 2-2015; 517-526
1554-8929
url http://hdl.handle.net/11336/3826
identifier_str_mv Faustino, André F; Guerra, Gabriela M.; Huber, Roland G.; Hollmann, Axel; Domingues, Marco M.; et al.; Understanding Dengue Virus Capsid Protein Disordered N‑Terminus and pep14-23-Based Inhibition; American Chemical Society; Acs Chemical Biology; 10; 2; 2-2015; 517-526
1554-8929
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/cb500640t
info:eu-repo/semantics/altIdentifier/issn/1554-8929
info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/DOI:10.1021/cb500640t
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/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_ 1842269205786787840
score 13.13397

Publicaciones similares