3wym

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<StructureSection load='3wym' size='340' side='right'caption='[[3wym]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='3wym' size='340' side='right'caption='[[3wym]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3wym]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WYM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WYM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3wym]] 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=3WYM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WYM FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3K9:1-[2-FLUORO-4-(1H-PYRAZOL-1-YL)PHENYL]-5-METHOXY-3-(1-PHENYL-1H-PYRAZOL-5-YL)PYRIDAZIN-4(1H)-ONE'>3K9</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&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3wyk|3wyk]], [[3wyl|3wyl]]</div></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=3K9:1-[2-FLUORO-4-(1H-PYRAZOL-1-YL)PHENYL]-5-METHOXY-3-(1-PHENYL-1H-PYRAZOL-5-YL)PYRIDAZIN-4(1H)-ONE'>3K9</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE10A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3wym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wym OCA], [https://pdbe.org/3wym PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wym RCSB], [https://www.ebi.ac.uk/pdbsum/3wym PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wym ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3wym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wym OCA], [https://pdbe.org/3wym PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wym RCSB], [https://www.ebi.ac.uk/pdbsum/3wym PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wym ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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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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[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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A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyri dazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (&gt;15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia.
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Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyri dazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor.,Kunitomo J, Yoshikawa M, Fushimi M, Kawada A, Quinn JF, Oki H, Kokubo H, Kondo M, Nakashima K, Kamiguchi N, Suzuki K, Kimura H, Taniguchi T J Med Chem. 2014 Nov 26;57(22):9627-43. doi: 10.1021/jm5013648. Epub 2014 Nov 10. PMID:25384088<ref>PMID:25384088</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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</div>
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<div class="pdbe-citations 3wym" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Hayano, Y]]
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[[Category: Hayano Y]]
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[[Category: Oki, H]]
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[[Category: Oki H]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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Current revision

Crystal structure of the catalytic domain of PDE10A complexed with 1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one

PDB ID 3wym

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OCA

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