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4y86

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Crystal structure of PDE9 in complex with racemic inhibitor C33

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Retrieved from "http://52.214.119.220/wiki/index.php/4y86"

Categories: Homo sapiens | Large Structures | Huang M

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 ==Crystal structure of PDE9 in complex with racemic inhibitor C33==
-<StructureSection load='4y86' size='340' side='right' caption='[[4y86]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
+<StructureSection load='4y86' size='340' side='right'caption='[[4y86]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4y86]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y86 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y86 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4y86]] 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=4Y86 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y86 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49D:6-{[(1S)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49D</scene>, <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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y87|4y87]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49D:6-{[(1S)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49D</scene>, <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>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE9A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4y86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y86 OCA], [https://pdbe.org/4y86 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y86 RCSB], [https://www.ebi.ac.uk/pdbsum/4y86 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y86 ProSAT]</span></td></tr>
-<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>
-<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=4y86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y86 OCA], [http://pdbe.org/4y86 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y86 RCSB], [http://www.ebi.ac.uk/pdbsum/4y86 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y86 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-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.
-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>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4y86" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
+[[Category: Large Structures]]
-[[Category: Huang, M]]
+[[Category: Huang M]]
-[[Category: Enantiomeric differentiation]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Inhibitor selectivity pocket]]
-[[Category: Pharmacokinetic]]
-[[Category: Phosphodiesterase 9a]]

4y86

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Crystal structure of PDE9 in complex with racemic inhibitor C33

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