View source for 4qge


==phosphodiesterase-9A in complex with inhibitor WYQ-C36D==
<StructureSection load='4qge' size='340' side='right'caption='[[4qge]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qge]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pan_troglodytes Pan troglodytes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QGE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QGE FirstGlance]. <br>
</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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35O:N~2~-(1-CYCLOPENTYL-4-OXO-4,7-DIHYDRO-1H-PYRAZOLO[3,4-D]PYRIMIDIN-6-YL)-N-(4-METHOXYPHENYL)-D-ALANINAMIDE'>35O</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4qge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qge OCA], [https://pdbe.org/4qge PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qge RCSB], [https://www.ebi.ac.uk/pdbsum/4qge PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qge ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PDE9A_PANTR PDE9A_PANTR] Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP. Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart. Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein. In brain, involved in cognitive function, such as learning and long-term memory.[UniProtKB:O76083][UniProtKB:Q8QZV1]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and &gt;150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.

Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent.,Shao YX, Huang M, Cui W, Feng LJ, Wu Y, Cai Y, Li Z, Zhu X, Liu P, Wan Y, Ke H, Luo HB J Med Chem. 2014 Dec 8. PMID:25432025<ref>PMID:25432025</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4qge" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Pan troglodytes]]
[[Category: Cui W]]
[[Category: Huang M]]
[[Category: Ke H]]
[[Category: Shao Y-X]]