Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/50761
Title: Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2
Authors: 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
Affilliation: 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.
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.
Abstract: 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.
Keywords: zinc-dependent Histone Deacetylases
Anti-parasitic
Cell Death
???metadata.dc.subject.fr???: Histone deacetylases
Mort cellulaire
Keywords in spanish: Histona Desacetilasas
Muerte Celular
keywords: HDACs
Antiparasitários
DeCS: Histona Desacetilases
Trypanosoma cruzi
Morte Celular
Issue Date: 2021
Publisher: Cell Press
Citation: 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.
DOI: 10.1016/j.celrep.2021.110129
ISSN: 2211-1247
Copyright: open access
Appears in Collections:PR - ICC - Artigos de Periódicos
MG - IRR - Artigos de Periódicos
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