4BZ5

Crystal structure of Schistosoma mansoni HDAC8

4BZ5 の概要

• エントリーDOI: 10.2210/pdb4bz5/pdb
• 関連するPDBエントリー: 4BZ6 4BZ7 4BZ8 4BZ9
• 分子名称: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, platyhelminths, inhibition
• 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: 202954.27

構造登録者

Marek, M.,Romier, C. (登録日: 2013-07-24, 公開日: 2013-08-14, 最終更新日: 2023-12-20)

主引用文献

Marek, M.,Kannan, S.,Hauser, A.,Moraes Mourao, M.,Caby, S.,Cura, V.,Stolfa, D.A.,Schmidtkunz, K.,Lancelot, J.,Andrade, L.,Renaud, J.,Oliveira, G.,Sippl, W.,Jung, M.,Cavarelli, J.,Pierce, R.J.,Romier, C.
Structural Basis for the Inhibition of Histone Deacetylase 8 (Hdac8), a Key Epigenetic Player in the Blood Fluke Schistosoma Mansoni.
Plos Pathog., 9:03645-, 2013

PubMed Abstract: The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.

PubMed: 24086136
DOI: 10.1371/JOURNAL.PPAT.1003645

実験手法

X-RAY DIFFRACTION (1.785 Å)