7P2S

Crystal structure of Schistosoma mansoni HDAC8 in complex with a tricyclic thieno[3,2-b]indole capped hydroxamate-based inhibitor, chlorine derivative

7P2S の概要

• エントリーDOI: 10.2210/pdb7p2s/pdb
• 分子名称: Histone deacetylase 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: inhibitor histone deacetylase (hdaci), complex schistosoma mansoni hdac8 + inhibitor, active-site., hydrolase
• 由来する生物種: Schistosoma mansoni (Blood fluke)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50402.33

構造登録者

Saccoccia, F.,Gemma, S.,Campiani, G.,Ruberti, G. (登録日: 2021-07-06, 公開日: 2022-07-27, 最終更新日: 2024-01-31)

主引用文献

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

PubMed 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 species, as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.

PubMed: 35970392
DOI: 10.1016/j.jbc.2022.102375

実験手法

X-RAY DIFFRACTION (2.2 Å)