7q1c
Crystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with a hydroxamate inhibitorCrystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with a hydroxamate inhibitor
Structural highlights
FunctionPublication Abstract from PubMedWriting 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. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.,Marek M, Ramos-Morales E, Picchi-Constante GFA, Bayer T, Norstrom C, Herp D, Sales-Junior PA, Guerra-Slompo EP, Hausmann K, Chakrabarti A, Shaik TB, Merz A, Troesch E, Schmidtkunz K, Goldenberg S, Pierce RJ, Mourao MM, Jung M, Schultz J, Sippl W, Zanchin NIT, Romier C Cell Rep. 2021 Dec 21;37(12):110129. doi: 10.1016/j.celrep.2021.110129. PMID:34936867[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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