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1z8a

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[[Image:1z8a.gif|left|200px]]<br /><applet load="1z8a" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1z8a, resolution 0.95&Aring;" />
 
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'''Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor'''<br />
 
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==Overview==
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==Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor==
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The crystal structure of a novel sulfonyl-pyridazinone inhibitor in complex with aldose reductase, the first enzyme of the polyol pathway, has been determined to 1.43 angstroms and 0.95 angstroms resolution. The ternary complex of inhibitor, cofactor and enzyme has been obtained by soaking of preformed crystals. Supposedly due to low solubility in the crystallisation buffer, in both structures the inhibitor shows reduced occupancy of 74% and 46% population, respectively. The pyridazinone head group of the inhibitor occupies the catalytic site, whereas the chloro-benzofuran moiety penetrates into the opened specificity pocket. The high-resolution structure provides some evidence that the pyridazinone group binds in a negatively charged deprotonated state, whereas the neighbouring His110 residue most likely adopts a neutral uncharged status. Since the latter structure is populated by the ligand to only 46%, a second conformation of the C-terminal ligand-binding region can be detected. This conformation corresponds to the closed state of the specificity pocket when no or only small ligands are bound to aldose reductase. The two conformational states are in good agreement with frames observed along a molecular dynamics trajectory describing the transition from closed to open situation. Accordingly, both geometries, superimposed in the averaged crystal structure, correspond to snapshots of the ligand-bound and the unbound state. Isothermal titration calorimetry has been applied to determine the binding constants of the investigated pyridazinone in comparison to the hydantoin sorbinil and the carboxylate-type inhibitors IDD 594 and tolrestat. The pyridazinone exhibits a binding affinity similar to those of tolrestat and sorbinil, and shows slightly reduced affinity compared to IDD 594. These studies elucidating the binding mode and providing information about protonation states of protein side-chains involved in binding of this novel class of inhibitors establish the platform for further structure-based drug design.
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<StructureSection load='1z8a' size='340' side='right'caption='[[1z8a]], [[Resolution|resolution]] 0.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1z8a]] 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=1Z8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Z8A 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]] 0.95&#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=62P:6-[(5-CHLORO-3-METHYL-1-BENZOFURAN-2-YL)SULFONYL]PYRIDAZIN-3(2H)-ONE'>62P</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=1z8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z8a OCA], [https://pdbe.org/1z8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1z8a RCSB], [https://www.ebi.ac.uk/pdbsum/1z8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1z8a ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ALDR_HUMAN ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
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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/z8/1z8a_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=1z8a 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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1Z8A 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 <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=62P:'>62P</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z8A OCA].
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*[[Aldose reductase 3D structures|Aldose reductase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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High-resolution crystal structure of aldose reductase complexed with the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative active site anchoring group., Steuber H, Zentgraf M, Podjarny A, Heine A, Klebe G, J Mol Biol. 2006 Feb 10;356(1):45-56. Epub 2005 Nov 10. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16337231 16337231]
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[[Category: Aldehyde reductase]]
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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: Heine, A.]]
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[[Category: Heine A]]
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[[Category: Klebe, G.]]
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[[Category: Klebe G]]
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[[Category: Podjarny, A.]]
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[[Category: Podjarny A]]
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[[Category: Steuber, H.]]
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[[Category: Steuber H]]
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[[Category: Zentgraf, M.]]
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[[Category: Zentgraf M]]
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[[Category: 62P]]
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[[Category: NAP]]
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[[Category: double conformation]]
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[[Category: protein-ligand complex]]
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[[Category: tim-barrel]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:13:01 2008''
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Current revision

Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor

PDB ID 1z8a

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