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==Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691== | ==Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691== | ||
<StructureSection load='3qi3' size='340' side='right' caption='[[3qi3]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='3qi3' size='340' side='right'caption='[[3qi3]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3qi3]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3qi3]] 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=3QI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QI3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PDB:1-(2-CHLOROPHENYL)-6-[(2R)-3,3,3-TRIFLUORO-2-METHYLPROPYL]-1,7-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>PDB</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" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PDB:1-(2-CHLOROPHENYL)-6-[(2R)-3,3,3-TRIFLUORO-2-METHYLPROPYL]-1,7-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>PDB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qi4|3qi4]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qi4|3qi4]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE, PDE9A ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE, PDE9A ([https://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'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qi3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qi3 OCA], [https://pdbe.org/3qi3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qi3 RCSB], [https://www.ebi.ac.uk/pdbsum/3qi3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qi3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Phosphodiesterase|Phosphodiesterase]] | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 30: | Line 30: | ||
[[Category: 3',5'-cyclic-GMP phosphodiesterase]] | [[Category: 3',5'-cyclic-GMP phosphodiesterase]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Hou, J]] | [[Category: Hou, J]] | ||
[[Category: Ke, H]] | [[Category: Ke, H]] | ||
Revision as of 09:09, 8 June 2022
Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691
Structural highlights
Function[PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.[1] Publication Abstract from PubMedPDE9 inhibitors show potential for treatment of diseases such as diabetes. To help with discovery of PDE9 inhibitors, we performed mutagenesis, kinetic, crystallographic, and molecular dynamics analyses on the active site residues of Gln453 and its stabilizing partner Glu406. The crystal structures of the PDE9 Q453E mutant (PDE9Q453E) in complex with inhibitors IBMX and (S)-BAY73-6691 showed asymmetric binding of the inhibitors in two subunits of the PDE9Q453E dimer and also the significant positional change of the M-loop at the active site. The kinetic analysis of the Q453E and E406A mutants suggested that the invariant glutamine is critical for binding of substrates and inhibitors, but is unlikely to play a key role in the differentiation between substrates of cGMP and cAMP. The molecular dynamics simulations suggest that residue Glu406 may be protonated and may thus explain the hydrogen bond distance between two side chain oxygens of Glu453 and Glu406 in the crystal structure of the PDE9Q453E mutant. The information from these studies may be useful for design of PDE9 inhibitors. Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic Acid, and role of the invariant glutamine.,Hou J, Xu J, Liu M, Zhao R, Luo HB, Ke H PLoS One. 2011 Mar 31;6(3):e18092. PMID:21483814[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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