1zkl

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(New page: 200px<br /> <applet load="1zkl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zkl, resolution 1.67&Aring;" /> '''Multiple Determinan...)
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[[Image:1zkl.gif|left|200px]]<br />
 
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<applet load="1zkl" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1zkl, resolution 1.67&Aring;" />
 
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'''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases'''<br />
 
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==Overview==
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==Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases==
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Phosphodiesterase (PDE) inhibitors have been widely studied as, therapeutics for treatment of human diseases. However, the mechanism by, which each PDE family recognizes selectively a category of inhibitors, remains a puzzle. Here we report the crystal structure of PDE7A1 catalytic, domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine, and kinetic analysis on the mutants of PDE7A1 and PDE4D2. Our studies, suggest at least three elements play critical roles in inhibitor, selectivity: 1) the conformation and position of an invariant glutamine, 2) the natures of scaffolding residues, and 3) residues that alter shape, and size of the binding pocket. Kinetic analysis shows that single PDE7 to, PDE4 mutations increase the sensitivity of PDE7 to PDE4 inhibitors but are, not sufficient to render the engineered enzymes comparable with the wild, types. The triple S373Y/S377T/I412S mutation of PDE7A1 produces a, PDE4-like enzyme, implying that multiple elements must work together to, determine inhibitor selectivity.
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<StructureSection load='1zkl' size='340' side='right'caption='[[1zkl]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1zkl]] 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=1ZKL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ZKL 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]] 1.67&#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=IBM:3-ISOBUTYL-1-METHYLXANTHINE'>IBM</scene>, <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=1zkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zkl OCA], [https://pdbe.org/1zkl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1zkl RCSB], [https://www.ebi.ac.uk/pdbsum/1zkl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1zkl ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PDE7A_HUMAN PDE7A_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction.<ref>PMID:19350606</ref>
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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/zk/1zkl_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=1zkl ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1ZKL 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, MG and IBM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ZKL OCA].
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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== References ==
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==Reference==
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<references/>
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Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7., Wang H, Liu Y, Chen Y, Robinson H, Ke H, J Biol Chem. 2005 Sep 2;280(35):30949-55. Epub 2005 Jul 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15994308 15994308]
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__TOC__
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[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
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</StructureSection>
[[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: Chen, Y.]]
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[[Category: Chen Y]]
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[[Category: Ke, H.]]
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[[Category: Ke H]]
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[[Category: Liu, Y.]]
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[[Category: Liu Y]]
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[[Category: Robinson, H.]]
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[[Category: Robinson H]]
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[[Category: Wang, H.]]
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[[Category: Wang H]]
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[[Category: IBM]]
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[[Category: MG]]
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[[Category: ZN]]
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[[Category: pde]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:35:57 2007''
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Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases

PDB ID 1zkl

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