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==Crystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with a hydroxamate inhibitor== | ==Crystal structure of Trypanosoma cruzi histone deacetylase DAC2 complexed with a hydroxamate inhibitor== | ||
<StructureSection load='7q1c' size='340' side='right'caption='[[7q1c]]' scene=''> | <StructureSection load='7q1c' size='340' side='right'caption='[[7q1c]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q1C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q1C FirstGlance]. <br> | <table><tr><td colspan='2'>[[7q1c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q1C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q1C FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q1c OCA], [https://pdbe.org/7q1c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q1c RCSB], [https://www.ebi.ac.uk/pdbsum/7q1c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q1c ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=T56:(E)-3-dibenzofuran-4-yl-N-oxidanyl-prop-2-enamide'>T56</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q1c OCA], [https://pdbe.org/7q1c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q1c RCSB], [https://www.ebi.ac.uk/pdbsum/7q1c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q1c ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:34936867</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7q1c" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Marek M]] | [[Category: Marek, M]] | ||
[[Category: Ramos-Morales E]] | [[Category: Ramos-Morales, E]] | ||
[[Category: Romier C]] | [[Category: Romier, C]] | ||
[[Category: Dac2]] | |||
[[Category: Epigenetic]] | |||
[[Category: Histone deacetylase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Pathogen]] | |||
[[Category: Trypanosoma cruzi]] | |||
Revision as of 10:15, 2 February 2022
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
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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