2wv8 | pdb_00002wv8

Complex of human dihydroorotate dehydrogenase with the inhibitor 221290

spinqualitylabelsall models 2wv8, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wv8 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, DDQ, FMN, ORO, SO4, VGN Related: 1d3h, 2b0m, 1d3g, 2bxv Activity: Dihydroorotate dehydrogenase (quinone), with EC number 1.3.5.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. Function [PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC(50) values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented. Inhibition of human DHODH by 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids identified by structure-guided fragment selection.,Fritzson I, Svensson B, Al-Karadaghi S, Walse B, Wellmar U, Nilsson UJ, da Graca Thrige D, Jonsson S ChemMedChem. 2010 Apr 6;5(4):608-17. PMID:20183850 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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