7Q1C

Crystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with a hydroxamate inhibitor

7Q1C の概要

• エントリーDOI: 10.2210/pdb7q1c/pdb
• 分子名称: Histone deacetylase DAC2, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: epigenetics, trypanosoma cruzi, histone deacetylase, dac2, pathogen, hydrolase
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 101611.21

構造登録者

Ramos-Morales, E.,Marek, M.,Romier, C. (登録日: 2021-10-18, 公開日: 2021-12-15, 最終更新日: 2024-01-31)

主引用文献

Marek, M.,Ramos-Morales, E.,Picchi-Constante, G.F.A.,Bayer, T.,Norstrom, C.,Herp, D.,Sales-Junior, P.A.,Guerra-Slompo, E.P.,Hausmann, K.,Chakrabarti, A.,Shaik, T.B.,Merz, A.,Troesch, E.,Schmidtkunz, K.,Goldenberg, S.,Pierce, R.J.,Mourao, M.M.,Jung, M.,Schultz, J.,Sippl, W.,Zanchin, N.I.T.,Romier, C.
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.
Cell Rep, 37:110129-110129, 2021

PubMed 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.

PubMed: 34936867
DOI: 10.1016/j.celrep.2021.110129

実験手法

X-RAY DIFFRACTION (2.3 Å)