| MAREK, Martin, E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM, D. HERP, P.A. SALES, E.P. GUERRA-SLOMPO, K. HAUSMANN, A. CHAKRABARTI, T.B. SHAIK, A. MERZ, E. TROESCH, K. SCHMIDTKUNZ, S. GOLDENBERG, R.J. PIERCE, MM MOURAO, M.M. JUNG, J. SCHULTZ, W. SIPPL, N.I.T. ZANCHIN and C. ROMIER. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. Cell Reports. CAMBRIDGE: Cell Press, 2021, vol. 37, No 12, p. 1-17, "e1-e9", 26 pp. ISSN 2211-1247. Available from: https://dx.doi.org/10.1016/j.celrep.2021.110129. |
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@article{1841382,
author = {Marek, Martin and RamosandMorales, E. and PicchiandConstante, G.F.A. and Bayer, T. and Norstrom, C. and Herp, D. and Sales, P.A. and GuerraandSlompo, E.P. and Hausmann, K. and Chakrabarti, A. and Shaik, T.B. and Merz, A. and Troesch, E. and Schmidtkunz, K. and Goldenberg, S. and Pierce, R.J. and Mourao, MM and Jung, M.M. and Schultz, J. and Sippl, W. and Zanchin, N.I.T. and Romier, C.},
article_location = {CAMBRIDGE},
article_number = {12},
doi = {http://dx.doi.org/10.1016/j.celrep.2021.110129},
keywords = {LYSINE ACETYLATION; HDAC INHIBITORS; IN-VITRO; PARASITES; POTENT; EPIGENETICS; EXPRESSION; MECHANISM; INSIGHTS; FEATURES},
language = {eng},
issn = {2211-1247},
journal = {Cell Reports},
title = {Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2},
url = {https://www.sciencedirect.com/science/article/pii/S2211124721016259?via%3Dihub},
volume = {37},
year = {2021}
}
TY - JOUR
ID - 1841382
AU - Marek, Martin - Ramos-Morales, E. - Picchi-Constante, G.F.A. - Bayer, T. - Norstrom, C. - Herp, D. - Sales, 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, MM - Jung, M.M. - Schultz, J. - Sippl, W. - Zanchin, N.I.T. - Romier, C.
PY - 2021
TI - Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2
JF - Cell Reports
VL - 37
IS - 12
SP - 1-17, "e1-e9"
EP - 1-17, "e1-e9"
PB - Cell Press
SN - 22111247
KW - LYSINE ACETYLATION
KW - HDAC INHIBITORS
KW - IN-VITRO
KW - PARASITES
KW - POTENT
KW - EPIGENETICS
KW - EXPRESSION
KW - MECHANISM
KW - INSIGHTS
KW - FEATURES
UR - https://www.sciencedirect.com/science/article/pii/S2211124721016259?via%3Dihub
N2 - 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 his tone 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.
ER -
MAREK, Martin, E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM, D. HERP, P.A. SALES, E.P. GUERRA-SLOMPO, K. HAUSMANN, A. CHAKRABARTI, T.B. SHAIK, A. MERZ, E. TROESCH, K. SCHMIDTKUNZ, S. GOLDENBERG, R.J. PIERCE, MM MOURAO, M.M. JUNG, J. SCHULTZ, W. SIPPL, N.I.T. ZANCHIN and C. ROMIER. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. \textit{Cell Reports}. CAMBRIDGE: Cell Press, 2021, vol.~37, No~12, p.~1-17, ''e1-e9'', 26 pp. ISSN~2211-1247. Available from: https://dx.doi.org/10.1016/j.celrep.2021.110129.
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