7p2v

Crystal structure of Schistosoma mansoni HDAC8 in complex with a 4-chlorophenyl-spiroindoline capped hydroxamate-based inhibitor, bound to a novel site

spinqualitylabelsall models 7p2v, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7p2v is a 1 chain structure with sequence from Schistosoma mansoni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: 4XI, K, PEG, TLA, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A5H660_SCHMA Publication Abstract from PubMed 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. 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. 2022 Aug 12:102375. doi: 10.1016/j.jbc.2022.102375. PMID:35970392 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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