7q1b
Crystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with QuisinostatCrystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with Quisinostat
Structural highlights
Publication 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. References
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