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https://www.arca.fiocruz.br/handle/icict/50761
SPECIES-SELECTIVE TARGETING OF PATHOGENS REVEALED BY THE ATYPICAL STRUCTURE AND ACTIVE SITE OF TRYPANOSOMA CRUZI HISTONE DEACETYLASE DAC2
Author
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
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.
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.
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