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| | ==Crystal structure of PDE5A1 in complex with icarisid II== | | ==Crystal structure of PDE5A1 in complex with icarisid II== |
| - | <StructureSection load='2h44' size='340' side='right' caption='[[2h44]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='2h44' size='340' side='right'caption='[[2h44]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2h44]] is a 1 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=2H44 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2H44 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2h44]] is a 1 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=2H44 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H44 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7CA:5,7-DIHYDROXY-2-(4-METHOXYPHENYL)-8-(3-METHYLBUTYL)-4-OXO-4H-CHROMEN-3-YL+6-DEOXY-ALPHA-L-MANNOPYRANOSIDE'>7CA</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2h40|2h40]], [[2h42|2h42]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CA:5,7-DIHYDROXY-2-(4-METHOXYPHENYL)-8-(3-METHYLBUTYL)-4-OXO-4H-CHROMEN-3-YL+6-DEOXY-ALPHA-L-MANNOPYRANOSIDE'>7CA</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">PDE5A, PDE5 ([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=2h44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h44 OCA], [https://pdbe.org/2h44 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h44 RCSB], [https://www.ebi.ac.uk/pdbsum/2h44 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h44 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>
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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=2h44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h44 OCA], [http://pdbe.org/2h44 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2h44 RCSB], [http://www.ebi.ac.uk/pdbsum/2h44 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2h44 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PDE5A_HUMAN PDE5A_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP. | + | [https://www.uniprot.org/uniprot/PDE5A_HUMAN PDE5A_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Phosphodiesterase|Phosphodiesterase]] | + | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 3',5'-cyclic-GMP phosphodiesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Ke, H]] | + | [[Category: Ke H]] |
| - | [[Category: Wang, H]] | + | [[Category: Wang H]] |
| - | [[Category: Flavonoid]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Icarisid ii]]
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| - | [[Category: Pde5a inhibitor]]
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| Structural highlights
Function
PDE5A_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35A upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.
Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.,Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H J Biol Chem. 2006 Jul 28;281(30):21469-79. Epub 2006 May 30. PMID:16735511[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H. Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem. 2006 Jul 28;281(30):21469-79. Epub 2006 May 30. PMID:16735511 doi:10.1074/jbc.M512527200
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