4QFC

Co-crystal structure of compound 3 (4-hydroxy-6-[2-(7-hydroxy-2-oxo-4-phenyl-2h-chromen-6-yl)ethyl]pyridazin-3(2h)-one) and FAD bound to human DAAO at 2.4A

4QFC の概要

• エントリーDOI: 10.2210/pdb4qfc/pdb
• 関連するPDBエントリー: 4QFD
• 分子名称: D-amino-acid oxidase, FLAVIN-ADENINE DINUCLEOTIDE, 4-hydroxy-6-[2-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)ethyl]pyridazin-3(2H)-one, ... (5 entities in total)
• 機能のキーワード: oxidase, oxidoreductase, daao, d-amino acid oxidase, fad dependent, nmdar, schizophrenia, d-serine competitive, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Peroxisome: P14920
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81404.74

構造登録者

Lukacs, C.M.,Chun, L. (登録日: 2014-05-20, 公開日: 2014-07-16, 最終更新日: 2023-09-20)

主引用文献

Terry-Lorenzo, R.T.,Chun, L.E.,Brown, S.P.,Heffernan, M.L.,Fang, Q.K.,Orsini, M.A.,Pollegioni, L.,Hardy, L.W.,Spear, K.L.,Large, T.H.
Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open conformation.
Biosci.Rep., 34:-, 2014

PubMed Abstract: The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since 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, 'compound 2' [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and 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.

PubMed: 25001371
DOI: 10.1042/BSR20140071

実験手法

X-RAY DIFFRACTION (2.4 Å)