4qfd

Co-crystal structure of compound 2 (3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid) and FAD bound to human DAAO at 2.85A

spinqualitylabelsall models 4qfd, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qfd is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 31R, FAD, NA Related: 4qfc Activity: D-amino-acid oxidase, with EC number 1.4.3.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [OXDA_HUMAN] Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids. Publication Abstract from PubMed The N-methyl-D-aspartate receptor (NMDAR) is a central regulator of synaptic plasticity and learning and memory. Human D-amino acid oxidase (hDAAO) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Because NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound 3-(7-Hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid ("compound 2"), which displayed low nM hDAAO inhibitory potency (Ki = 7 nM). While the library was expected to enrich for compounds that were competitive for both D-serine and flavin adenine dinucleotide (FAD), compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active site lid was in an open position. These results confirm previous hypotheses regarding active site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors. Novel Human D-Amino Acid Oxidase Inhibitors Stabilize an Active Site Lid Open Conformation.,Terry-Lorenzo RT, Chun LE, Brown SP, Heffernan ML, Fang QK, Orsini MA, Pollegioni L, Hardy LW, Spear KL, Large TH Biosci Rep. 2014 Jul 8. PMID:25001371 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Amino acid oxidase

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