4CQF
Crystal structure of Schistosoma mansoni HDAC8 complexed with a mercaptoacetamide inhibitor
Summary for 4CQF
| Entry DOI | 10.2210/pdb4cqf/pdb |
| Descriptor | HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (7 entities in total) |
| Functional Keywords | hydrolase, structural protein, eukaryotes, platyhelminths, epigenetics, histone deacetylases, inhibition |
| Biological source | SCHISTOSOMA MANSONI |
| Total number of polymer chains | 4 |
| Total formula weight | 204924.16 |
| Authors | Marek, M.,Romier, C. (deposition date: 2014-02-14, release date: 2014-04-02, Last modification date: 2023-12-20) |
| Primary citation | Stolfa, D.A.,Marek, M.,Lancelot, J.,Hauser, A.T.,Walter, A.,Leproult, E.,Melesina, J.,Rumpf, T.,Wurtz, J.M.,Cavarelli, J.,Sippl, W.,Pierce, R.J.,Romier, C.,Jung, M. Molecular Basis for the Anti-Parasitic Activity of a Mercaptoacetamide Derivative that Inhibits Histone Deacetylase 8 (Hdac8) from the Human Pathogen Schistosoma Mansoni J.Mol.Biol., 426:3442-, 2014 Cited by PubMed Abstract: Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here, we present results on the investigations of a focused set of HDAC (histone deacetylase) inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol-based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structure of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore, this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited antiparasitic activity on cultured schistosomes in a dose-dependent manner. PubMed: 24657767DOI: 10.1016/J.JMB.2014.03.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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