4qfc: Difference between revisions
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==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== | ==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== | ||
<StructureSection load='4qfc' size='340' side='right' caption='[[4qfc]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='4qfc' size='340' side='right'caption='[[4qfc]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4qfc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QFC OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4qfc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QFC FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=31T:4-HYDROXY-6-[2-(7-HYDROXY-2-OXO-4-PHENYL-2H-CHROMEN-6-YL)ETHYL]PYRIDAZIN-3(2H)-ONE'>31T</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=31T:4-HYDROXY-6-[2-(7-HYDROXY-2-OXO-4-PHENYL-2H-CHROMEN-6-YL)ETHYL]PYRIDAZIN-3(2H)-ONE'>31T</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> | |||
<tr | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qfc OCA], [https://pdbe.org/4qfc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qfc RCSB], [https://www.ebi.ac.uk/pdbsum/4qfc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qfc ProSAT]</span></td></tr> | ||
</table> | |||
<table> | == Function == | ||
[https://www.uniprot.org/uniprot/OXDA_HUMAN 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.<ref>PMID:17303072</ref> | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4qfc" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Amino acid oxidase 3D structures|Amino acid oxidase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Chun L]] | ||
[[Category: | [[Category: Lukacs CM]] | ||
Latest revision as of 20:31, 20 September 2023
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 2.4ACo-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
Structural highlights
FunctionOXDA_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.[1] Publication Abstract from PubMedThe 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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