2h40

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(New page: 200px<br /> <applet load="2h40" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h40, resolution 1.85&Aring;" /> '''Crystal structure o...)
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[[Image:2h40.gif|left|200px]]<br />
 
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<applet load="2h40" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2h40, resolution 1.85&Aring;" />
 
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'''Crystal structure of the catalytic domain of unliganded PDE5'''<br />
 
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==Overview==
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==Crystal structure of the catalytic domain of unliganded PDE5==
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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.
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<StructureSection load='2h40' size='340' side='right'caption='[[2h40]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2h40]] 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=2H40 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H40 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]] 1.85&#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=ZN:ZINC+ION'>ZN</scene></td></tr>
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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=2h40 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h40 OCA], [https://pdbe.org/2h40 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h40 RCSB], [https://www.ebi.ac.uk/pdbsum/2h40 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h40 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/h4/2h40_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=2h40 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:16735511</ref>
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2H40 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and MG as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2H40 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16735511 16735511]
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</div>
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[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
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<div class="pdbe-citations 2h40" style="background-color:#fffaf0;"></div>
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[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Cai, J.]]
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[[Category: Corbin, J.D.]]
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[[Category: Francis, S.H.]]
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[[Category: Huai, Q.]]
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[[Category: Ke, H.]]
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[[Category: Lin, G.]]
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[[Category: Liu, Y.]]
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[[Category: Robinson, H.]]
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[[Category: Wang, H.]]
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[[Category: Xin, Z.]]
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[[Category: Zoraghi, R.]]
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[[Category: MG]]
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[[Category: ZN]]
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[[Category: pde5]]
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[[Category: unliganded]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:25:50 2007''
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==See Also==
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Cai J]]
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[[Category: Corbin JD]]
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[[Category: Francis SH]]
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[[Category: Huai Q]]
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[[Category: Ke H]]
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[[Category: Lin G]]
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[[Category: Liu Y]]
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[[Category: Robinson H]]
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[[Category: Wang H]]
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[[Category: Xin Z]]
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[[Category: Zoraghi R]]

Current revision

Crystal structure of the catalytic domain of unliganded PDE5

PDB ID 2h40

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