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Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors.

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Saccoccia F, Pozzetti L, Gimmelli R, Butini S, Guidi A, Papoff G, Giannaccari M, Brogi S, Scognamiglio V, Gemma S, Ruberti G, Campiani G
OpenAccess logo J Biol Chem 102375 (2022)
Related entries: 7p2s, 7p2t, 7p2u, 7p2v

Cited: 2 times
EuropePMC logo PMID: 35970392

Abstract

Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases. Schistosoma mansoni HDAC8 (SmHDAC8) is highly expressed in all life cycle stages of the parasite and selective inhibition is required in order to avoid undesirable off-target effects in the host. Herein, by X-ray crystal structures of SmHDAC8-inhibitor complexes, biochemical and phenotypic studies, we found two schistosomicidal spiroindoline-derivatives binding a novel site, next to Trp198, on the enzyme surface. We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma spp., as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.

Articles - 7poz mentioned but not cited (1)

  1. Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors. Saccoccia F, Pozzetti L, Gimmelli R, Butini S, Guidi A, Papoff G, Giannaccari M, Brogi S, Scognamiglio V, Gemma S, Ruberti G, Campiani G. J Biol Chem 298 102375 (2022)


Articles citing this publication (1)

  1. Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation. Alzain AA, Mukhtar RM, Abdelmoniem N, Elbadwi FA, Hussien A, Garelnabi EAE, Osman W, Sherif AE, Khedr AIM, Ghazawi KF, Samman WA, Ibrahim SRM, Mohamed GA, Ashour A. Metabolites 13 658 (2023)


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