Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.

Detalhes bibliográficos
Autor(a) principal: Marek, Martin
Data de Publicação: 2013
Outros Autores: Kannan, Srinivasaraghavan, Hauser, Alexander-Thomas, Mourão, Marina Moraes, Caby, Stéphanie, Cura, Vincent, Stolfa, Diana A., Schmidtkunz, Karin, Lancelot, Julien, Andrade, Luiza A, Renaud, Jean-Paul, Oliveira, Guilherme Correa de, Sippl, Wolfgang, Jung, Manfred, Cavarelli, Jean, Pierce, Raymond John, Romier, Christophe
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/30009
Resumo: Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, France
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spelling Marek, MartinKannan, SrinivasaraghavanHauser, Alexander-ThomasMourão, Marina MoraesCaby, StéphanieCura, VincentStolfa, Diana A.Schmidtkunz, KarinLancelot, JulienAndrade, Luiza ARenaud, Jean-PaulOliveira, Guilherme Correa deSippl, WolfgangJung, ManfredCavarelli, JeanPierce, Raymond JohnRomier, Christophe2018-11-13T12:45:56Z2018-11-13T12:45:56Z2013MAREK, Martin et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. PLoS Pathog., v. 9n. 9, e1003645, 20131553-7366https://www.arca.fiocruz.br/handle/icict/3000910.1371/journal.ppat.1003645engPublic Library of ScienceEsquistossomossedoenças parasitáriasSchistosoma mansoniSchistosomaParasitic diseasesSchistosoma mansoniEnzyme structurephenylalanineZincEnzyme inhibitorsEpigeneticsStructural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, FranceInstitut für Pharmazie. Martin-Luther-Universität Halle-Wittenberg. Halle, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais. Centro de Excelência em Bioinformática. Grupo de Genômica e Biologia Computacional. Belo Horizonte, MG, BrazilInstitut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Freiburg Institute of Advanced Studies (FRIAS), Albert-Ludwigs-Universität Freiburg, Freiburg, GermanyInstitut für Pharmazeutische Wissenschaften. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany/Freiburg Institute of Advanced Studies. Albert-Ludwigs-Universität Freiburg. Freiburg, GermanyDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceCenter for Infection and Immunity of Lille. Université Lille Nord de France. Institut Pasteur de Lille. Lille, FranceDépartement de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire. Université de Strasbourg. Illkirch, FranceThe treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogensinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83082https://www.arca.fiocruz.br/bitstream/icict/30009/1/license.txt9193a7c197bc67acd023525e72a03240MD51ORIGINALStructural Basis for the Inhibition of Histone .pdfStructural Basis for the Inhibition of Histone .pdfapplication/pdf10051721https://www.arca.fiocruz.br/bitstream/icict/30009/2/Structural%20Basis%20for%20the%20Inhibition%20of%20Histone%20.pdf36ced7239c061ef58937ef2728effa22MD52TEXTStructural Basis for the Inhibition of Histone .pdf.txtStructural Basis for the Inhibition 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dc.title.pt_BR.fl_str_mv Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
title Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
spellingShingle Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
Marek, Martin
Esquistossomosse
doenças parasitárias
Schistosoma mansoni
Schistosoma
Parasitic diseases
Schistosoma mansoni
Enzyme structure
phenylalanine
Zinc
Enzyme inhibitors
Epigenetics
title_short Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
title_full Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
title_fullStr Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
title_full_unstemmed Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
title_sort Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
author Marek, Martin
author_facet Marek, Martin
Kannan, Srinivasaraghavan
Hauser, Alexander-Thomas
Mourão, Marina Moraes
Caby, Stéphanie
Cura, Vincent
Stolfa, Diana A.
Schmidtkunz, Karin
Lancelot, Julien
Andrade, Luiza A
Renaud, Jean-Paul
Oliveira, Guilherme Correa de
Sippl, Wolfgang
Jung, Manfred
Cavarelli, Jean
Pierce, Raymond John
Romier, Christophe
author_role author
author2 Kannan, Srinivasaraghavan
Hauser, Alexander-Thomas
Mourão, Marina Moraes
Caby, Stéphanie
Cura, Vincent
Stolfa, Diana A.
Schmidtkunz, Karin
Lancelot, Julien
Andrade, Luiza A
Renaud, Jean-Paul
Oliveira, Guilherme Correa de
Sippl, Wolfgang
Jung, Manfred
Cavarelli, Jean
Pierce, Raymond John
Romier, Christophe
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Marek, Martin
Kannan, Srinivasaraghavan
Hauser, Alexander-Thomas
Mourão, Marina Moraes
Caby, Stéphanie
Cura, Vincent
Stolfa, Diana A.
Schmidtkunz, Karin
Lancelot, Julien
Andrade, Luiza A
Renaud, Jean-Paul
Oliveira, Guilherme Correa de
Sippl, Wolfgang
Jung, Manfred
Cavarelli, Jean
Pierce, Raymond John
Romier, Christophe
dc.subject.other.pt_BR.fl_str_mv Esquistossomosse
doenças parasitárias
Schistosoma mansoni
topic Esquistossomosse
doenças parasitárias
Schistosoma mansoni
Schistosoma
Parasitic diseases
Schistosoma mansoni
Enzyme structure
phenylalanine
Zinc
Enzyme inhibitors
Epigenetics
dc.subject.en.pt_BR.fl_str_mv Schistosoma
Parasitic diseases
Schistosoma mansoni
Enzyme structure
phenylalanine
Zinc
Enzyme inhibitors
Epigenetics
description Département de Biologie Structurale Intégrative. Institut de Génétique et Biologie Moléculaire et Cellulaire.Université de Strasbourg. Illkirch, France
publishDate 2013
dc.date.issued.fl_str_mv 2013
dc.date.accessioned.fl_str_mv 2018-11-13T12:45:56Z
dc.date.available.fl_str_mv 2018-11-13T12:45:56Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv MAREK, Martin et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. PLoS Pathog., v. 9n. 9, e1003645, 2013
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/30009
dc.identifier.issn.pt_BR.fl_str_mv 1553-7366
dc.identifier.doi.none.fl_str_mv 10.1371/journal.ppat.1003645
identifier_str_mv MAREK, Martin et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni. PLoS Pathog., v. 9n. 9, e1003645, 2013
1553-7366
10.1371/journal.ppat.1003645
url https://www.arca.fiocruz.br/handle/icict/30009
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
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institution FIOCRUZ
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collection Repositório Institucional da FIOCRUZ (ARCA)
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