4BZ5

Crystal structure of Schistosoma mansoni HDAC8

Summary for 4BZ5

• Entry DOI: 10.2210/pdb4bz5/pdb
• Related: 4BZ6 4BZ7 4BZ8 4BZ9
• Descriptor: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase, platyhelminths, inhibition
• Biological source: SCHISTOSOMA MANSONI
• Total number of polymer chains: 4
• Total formula weight: 202954.27

Authors

Marek, M.,Romier, C. (deposition date: 2013-07-24, release date: 2013-08-14, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.785 Å)