4y8c: Difference between revisions
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==Crystal structure of phosphodiesterase 9 in complex with (S)-C33== | ==Crystal structure of phosphodiesterase 9 in complex with (S)-C33== | ||
<StructureSection load='4y8c' size='340' side='right' caption='[[4y8c]], [[Resolution|resolution]] 2.70Å' scene=''> | <StructureSection load='4y8c' size='340' side='right' caption='[[4y8c]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4y8c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8C FirstGlance]. <br> | <table><tr><td colspan='2'>[[4y8c]] 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=4Y8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8C 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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </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=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='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='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=4y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8c OCA], [http://pdbe.org/4y8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y8c RCSB], [http://www.ebi.ac.uk/pdbsum/4y8c PDBsum]</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=4y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8c OCA], [http://pdbe.org/4y8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y8c RCSB], [http://www.ebi.ac.uk/pdbsum/4y8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y8c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: 3',5'-cyclic-GMP phosphodiesterase]] | [[Category: 3',5'-cyclic-GMP phosphodiesterase]] | ||
[[Category: Human]] | |||
[[Category: Huang, M]] | [[Category: Huang, M]] | ||
[[Category: Enantiomeric differentiation]] | [[Category: Enantiomeric differentiation]] | ||
Revision as of 20:02, 16 November 2017
Crystal structure of phosphodiesterase 9 in complex with (S)-C33Crystal structure of phosphodiesterase 9 in complex with (S)-C33
Structural highlights
Function[PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.[1] Publication Abstract from PubMedPhosphodiesterase-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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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