6uy4

Crystal structure of dihydroorotate dehydrogenase from Schistosoma mansoni

spinqualitylabelsall models 6uy4, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6uy4 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 2.796Å Ligands: FMN, GOL, QLA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function G4VFD7_SCHMA Publication Abstract from PubMed Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target-based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone-analog inhibitor 2-((4-fluorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (QLA). We discuss three major findings: 1) the open conformation of the active site-loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; 2) The presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; 3) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs, and provides the molecular basis for structure-guided design of SmDHODH inhibitors. Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni.,Mori RM, Aleixo MAA, Zapata LCC, Calil FA, Emery FDS, Nonato MC FEBS J. 2020 May 19. doi: 10.1111/febs.15367. PMID:32428996 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydroorotate dehydrogenase 3D structures

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