3bjc

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[[Image:3bjc.jpg|left|200px]]
 
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==Crystal structure of the PDE5A catalytic domain in complex with a novel inhibitor==
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The line below this paragraph, containing "STRUCTURE_3bjc", creates the "Structure Box" on the page.
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<StructureSection load='3bjc' size='340' side='right'caption='[[3bjc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3bjc]] 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=3BJC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BJC FirstGlance]. <br>
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</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>
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<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=WAN:5-ETHOXY-4-(1-METHYL-7-OXO-3-PROPYL-6,7-DIHYDRO-1H-PYRAZOLO[4,3-D]PYRIMIDIN-5-YL)THIOPHENE-2-SULFONAMIDE'>WAN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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{{STRUCTURE_3bjc| PDB=3bjc | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bjc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bjc OCA], [https://pdbe.org/3bjc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bjc RCSB], [https://www.ebi.ac.uk/pdbsum/3bjc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bjc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bj/3bjc_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3bjc ConSurf].
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<div style="clear:both"></div>
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'''Crystal structure of the PDE5A catalytic domain in complex with a novel inhibitor'''
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==See Also==
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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__TOC__
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==Overview==
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</StructureSection>
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Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyra zolo[4,3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5A. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required.
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==About this Structure==
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3BJC is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BJC OCA].
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==Reference==
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An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies., Chen G, Wang H, Robinson H, Cai J, Wan Y, Ke H, Biochem Pharmacol. 2008 May 1;75(9):1717-28. Epub 2008 Feb 12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18346713 18346713]
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[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Cai, J.]]
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[[Category: Cai J]]
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[[Category: Chen, G.]]
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[[Category: Chen G]]
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[[Category: Howard, R.]]
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[[Category: Howard R]]
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[[Category: Ke, H.]]
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[[Category: Ke H]]
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[[Category: Wan, Y.]]
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[[Category: Wan Y]]
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[[Category: Wang, H.]]
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[[Category: Wang H]]
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[[Category: Allosteric enzyme]]
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[[Category: Alternative splicing]]
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[[Category: Cgmp]]
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[[Category: Cgmp-binding]]
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[[Category: Crystal structure]]
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[[Category: Erectile dysfunction]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor design]]
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[[Category: Magnesium]]
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[[Category: Metal-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: Pde5]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:32:45 2008''
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Current revision

Crystal structure of the PDE5A catalytic domain in complex with a novel inhibitor

PDB ID 3bjc

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