Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | por |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/50761 |
Resumo: | Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France. |
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Marek, MartinRamos-Morales, ElizabethPicchi-Constante, Gisele Fernanda AssineBayer, TheresaNorström, CarinaHerp, DanielSales-Junior, Policarpo A.Guerra-Slompo, Eloise PavãoHausmann, KristinChakrabarti, AloktaShaik, Tajith B.Merz, AnnikaTroesch, EdouardSchmidtkunz, KarinGoldenberg, SamuelPierce, Raymond J.Mourão, Marina M.Jung, ManfredSchultz, JohanSippl, WolfgangZanchin, Nilson Ivo ToninRomier, Christophe2022-01-14T19:48:38Z2022-01-14T19:48:38Z2021MAREK, Martin et al. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. Cell Reports v. 37, n. 110129, p. 1–27, 2021.2211-1247https://www.arca.fiocruz.br/handle/icict/5076110.1016/j.celrep.2021.110129porCell PressHDACsAntiparasitárioszinc-dependent Histone DeacetylasesAnti-parasiticCell DeathHistona DesacetilasasMuerte CelularHistone deacetylasesMort cellulaireHistona DesacetilasesTrypanosoma cruziMorte CelularSpecies-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversité de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France.Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Institute of Pharmacy. Martin-Luther-Universität Halle-Wittenberg. Halle (Saale), Germany.Kancera AB. Karolinska Institutet Science Park. Solna, Sweden.Institute of Pharmaceutical Sciences. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Institute of Pharmacy. Martin-Luther-Universität Halle-Wittenberg. Halle (Saale), Germany.Institute of Pharmaceutical Sciences. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany.Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France.Institute of Pharmaceutical Sciences. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany.Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France.Institute of Pharmaceutical Sciences. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Université de Lille, CNRS, INSERM, CHU Lille. Lille, France. / Institut Pasteur de Lille. Lille, France. / CIIL - Centre d’Infection et d’Immunité de Lille. Lille, France.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Institute of Pharmaceutical Sciences. Albert-Ludwigs-Universität Freiburg. Freiburg, Germany.Kancera AB. Karolinska Institutet Science Park. Solna, Sweden.Institute of Pharmacy. Martin-Luther-Universität Halle-Wittenberg. Halle (Saale), Germany.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France.Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens’ modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83084https://www.arca.fiocruz.br/bitstream/icict/50761/1/license.txt783568c2893d2e25a99990b126be1772MD51ORIGINAL1-s2.0-S2211124721016259-mainOK.pdf1-s2.0-S2211124721016259-mainOK.pdfapplication/pdf7544259https://www.arca.fiocruz.br/bitstream/icict/50761/2/1-s2.0-S2211124721016259-mainOK.pdf07e96e6d7a8f535525366a05a94e5181MD52icict/507612022-01-14 16:48:38.508oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352022-01-14T19:48:38Repositório Institucional da FIOCRUZ (ARCA) - 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| dc.title.pt_BR.fl_str_mv |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| title |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| spellingShingle |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 Marek, Martin HDACs Antiparasitários zinc-dependent Histone Deacetylases Anti-parasitic Cell Death Histona Desacetilasas Muerte Celular Histone deacetylases Mort cellulaire Histona Desacetilases Trypanosoma cruzi Morte Celular |
| title_short |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| title_full |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| title_fullStr |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| title_full_unstemmed |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| title_sort |
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 |
| author |
Marek, Martin |
| author_facet |
Marek, Martin Ramos-Morales, Elizabeth Picchi-Constante, Gisele Fernanda Assine Bayer, Theresa Norström, Carina Herp, Daniel Sales-Junior, Policarpo A. Guerra-Slompo, Eloise Pavão Hausmann, Kristin Chakrabarti, Alokta Shaik, Tajith B. Merz, Annika Troesch, Edouard Schmidtkunz, Karin Goldenberg, Samuel Pierce, Raymond J. Mourão, Marina M. Jung, Manfred Schultz, Johan Sippl, Wolfgang Zanchin, Nilson Ivo Tonin Romier, Christophe |
| author_role |
author |
| author2 |
Ramos-Morales, Elizabeth Picchi-Constante, Gisele Fernanda Assine Bayer, Theresa Norström, Carina Herp, Daniel Sales-Junior, Policarpo A. Guerra-Slompo, Eloise Pavão Hausmann, Kristin Chakrabarti, Alokta Shaik, Tajith B. Merz, Annika Troesch, Edouard Schmidtkunz, Karin Goldenberg, Samuel Pierce, Raymond J. Mourão, Marina M. Jung, Manfred Schultz, Johan Sippl, Wolfgang Zanchin, Nilson Ivo Tonin Romier, Christophe |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Marek, Martin Ramos-Morales, Elizabeth Picchi-Constante, Gisele Fernanda Assine Bayer, Theresa Norström, Carina Herp, Daniel Sales-Junior, Policarpo A. Guerra-Slompo, Eloise Pavão Hausmann, Kristin Chakrabarti, Alokta Shaik, Tajith B. Merz, Annika Troesch, Edouard Schmidtkunz, Karin Goldenberg, Samuel Pierce, Raymond J. Mourão, Marina M. Jung, Manfred Schultz, Johan Sippl, Wolfgang Zanchin, Nilson Ivo Tonin Romier, Christophe |
| dc.subject.other.pt_BR.fl_str_mv |
HDACs Antiparasitários |
| topic |
HDACs Antiparasitários zinc-dependent Histone Deacetylases Anti-parasitic Cell Death Histona Desacetilasas Muerte Celular Histone deacetylases Mort cellulaire Histona Desacetilases Trypanosoma cruzi Morte Celular |
| dc.subject.en.pt_BR.fl_str_mv |
zinc-dependent Histone Deacetylases Anti-parasitic Cell Death |
| dc.subject.es.pt_BR.fl_str_mv |
Histona Desacetilasas Muerte Celular |
| dc.subject.fr.pt_BR.fl_str_mv |
Histone deacetylases Mort cellulaire |
| dc.subject.decs.pt_BR.fl_str_mv |
Histona Desacetilases Trypanosoma cruzi Morte Celular |
| description |
Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Illkirch, France. / Université de Strasbourg, CNRS, INSERM. Institut de Génétique et de Biologie Moléculaire et Cellulaire. Department of Integrated Structural Biology. Illkirch, France. |
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2021 |
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2021 |
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2022-01-14T19:48:38Z |
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2022-01-14T19:48:38Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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MAREK, Martin et al. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. Cell Reports v. 37, n. 110129, p. 1–27, 2021. |
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https://www.arca.fiocruz.br/handle/icict/50761 |
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2211-1247 |
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10.1016/j.celrep.2021.110129 |
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MAREK, Martin et al. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. Cell Reports v. 37, n. 110129, p. 1–27, 2021. 2211-1247 10.1016/j.celrep.2021.110129 |
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Cell Press |
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Cell Press |
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