4xy2

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==Crystal structure of PDE10A in complex with ASP9436==
==Crystal structure of PDE10A in complex with ASP9436==
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<StructureSection load='4xy2' size='340' side='right' caption='[[4xy2]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
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<StructureSection load='4xy2' size='340' side='right'caption='[[4xy2]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4xy2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XY2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XY2 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4xy2]] 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=4XY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XY2 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=490:1-METHYL-5-(1-METHYL-3-{[4-(1-METHYL-1H-BENZIMIDAZOL-4-YL)PHENOXY]METHYL}-1H-PYRAZOL-4-YL)PYRIDIN-2(1H)-ONE'>490</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xy2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xy2 RCSB], [http://www.ebi.ac.uk/pdbsum/4xy2 PDBsum]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=490:1-METHYL-5-(1-METHYL-3-{[4-(1-METHYL-1H-BENZIMIDAZOL-4-YL)PHENOXY]METHYL}-1H-PYRAZOL-4-YL)PYRIDIN-2(1H)-ONE'>490</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4xy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xy2 OCA], [https://pdbe.org/4xy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xy2 RCSB], [https://www.ebi.ac.uk/pdbsum/4xy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xy2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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[https://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyra zol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.
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Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.,Hamaguchi W, Masuda N, Miyamoto S, Kikuchi S, Narazaki F, Shiina Y, Seo R, Amano Y, Mihara T, Moriguchi H, Hattori K Bioorg Med Chem. 2015 Jul 1;23(13):3351-67. doi: 10.1016/j.bmc.2015.04.052. Epub , 2015 Apr 25. PMID:25960322<ref>PMID:25960322</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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*[[Phosphofructokinase 3D structures|Phosphofructokinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Amano, Y]]
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[[Category: Homo sapiens]]
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[[Category: Honbou, K]]
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[[Category: Large Structures]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Amano Y]]
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[[Category: Phosphodiesterase]]
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[[Category: Honbou K]]

Current revision

Crystal structure of PDE10A in complex with ASP9436

PDB ID 4xy2

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