4y87

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==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==
==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==
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<StructureSection load='4y87' size='340' side='right' caption='[[4y87]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
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<StructureSection load='4y87' size='340' side='right'caption='[[4y87]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4y87]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y87 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=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</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]] 3.1&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y86|4y86]]</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=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </span></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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [https://pdbe.org/4y87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [https://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 ProSAT]</span></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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [http://pdbe.org/4y87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [http://www.ebi.ac.uk/pdbsum/4y87 PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN]] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
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[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazo lo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.
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Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.,Huang M, Shao Y, Hou J, Cui W, Liang B, Huang Y, Li Z, Wu Y, Zhu X, Liu P, Wan Y, Ke H, Luo HB Mol Pharmacol. 2015 Nov;88(5):836-45. doi: 10.1124/mol.115.099747. Epub 2015 Aug , 27. PMID:26316540<ref>PMID:26316540</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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<div class="pdbe-citations 4y87" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
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[[Category: Homo sapiens]]
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[[Category: Huang, M]]
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[[Category: Large Structures]]
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[[Category: Enantiomeric differentiation]]
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[[Category: Huang M]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Inhibitor selectivity pocket]]
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[[Category: Pharmacokinetic]]
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[[Category: Phosphodiesterase 9a]]
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Current revision

Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)

PDB ID 4y87

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