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

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.
PDB ID: 4QFDDownload
MMDB ID: 121575
PDB Deposition Date: 2014/5/20
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.85  Å
Source Organism:
Similar Structures:
Biological Unit for 4QFD: dimeric; determined by author and by software (PISA)
Molecular Components in 4QFD
Label Count Molecule
Proteins (2 molecules)
D-amino-acid Oxidase(Gene symbol: DAO)
Molecule annotation
Chemicals (6 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB