6GXA

Crystal structure of Schistosoma mansoni HDAC8 complexed with an hydroxamate 2

6GXA の概要

• エントリーDOI: 10.2210/pdb6gxa/pdb
• 分子名称: Histone deacetylase, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• 機能のキーワード: epigenetics, histone deacetylase, hdac8, selective inhibitor, pathogen, hydrolase
• 由来する生物種: Schistosoma mansoni
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 204392.85

構造登録者

Shaik, T.B.,Marek, M.,Romier, C. (登録日: 2018-06-27, 公開日: 2018-08-15, 最終更新日: 2024-01-17)

主引用文献

Bayer, T.,Chakrabarti, A.,Lancelot, J.,Shaik, T.B.,Hausmann, K.,Melesina, J.,Schmidtkunz, K.,Marek, M.,Erdmann, F.,Schmidt, M.,Robaa, D.,Romier, C.,Pierce, R.J.,Jung, M.,Sippl, W.
Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis.
ChemMedChem, 13:1517-1529, 2018

PubMed Abstract: Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of Schistosoma mansoni histone deacetylase 8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Two of the compounds showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.

PubMed: 29806110
DOI: 10.1002/cmdc.201800238

実験手法

X-RAY DIFFRACTION (2.1 Å)