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1pwl

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Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat

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-[[Image:1pwl.jpg|left|200px]]
- {{Structure
+==Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat==
-|PDB= 1pwl |SIZE=350|CAPTION= <scene name='initialview01'>1pwl</scene>, resolution 1.10&Aring;
+<StructureSection load='1pwl' size='340' side='right'caption='[[1pwl]], [[Resolution|resolution]] 1.10&Aring;' scene=''>
-|SITE=
+== Structural highlights ==
-|LIGAND= <scene name='pdbligand=1GL:4-O-METHYL-2,6-DIDEOXY-ALPHA-D-GALACTO-HEXOPYRANOSE'>1GL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>
+<table><tr><td colspan='2'>[[1pwl]] 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=1PWL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PWL FirstGlance]. <br>
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.1&#8491;</td></tr>
-|GENE=
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BFI:2[4-BROMO-2-FLUOROPHENYL)METHYL]-6-FLUOROSPIRO[ISOQUINOLINE-4-(1H),3-PYRROLIDINE]-1,2,3,5(2H)-TETRONE'>BFI</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
-|DOMAIN=
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pwl OCA], [https://pdbe.org/1pwl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pwl RCSB], [https://www.ebi.ac.uk/pdbsum/1pwl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pwl ProSAT]</span></td></tr>
-|RELATEDENTRY=[[1pwm|1PWM]]
+</table>
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pwl OCA], [http://www.ebi.ac.uk/pdbsum/1pwl PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pwl RCSB]</span>
+== Function ==
-}}
+[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.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pw/1pwl_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=1pwl ConSurf].
+<div style="clear:both"></div>
-'''Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat'''
+==See Also==
+*[[Aldose reductase 3D structures|Aldose reductase 3D structures]]
+__TOC__
-==Overview==
+</StructureSection>
-The X-ray structures of human aldose reductase holoenzyme in complex with the inhibitors Fidarestat (SNK-860) and Minalrestat (WAY-509) were determined at atomic resolutions of 0.92 A and 1.1 A, respectively. The hydantoin and succinimide moieties of the inhibitors interacted with the conserved anion-binding site located between the nicotinamide ring of the coenzyme and active site residues Tyr48, His110, and Trp111. Minalrestat's hydrophobic isoquinoline ring was bound in an adjacent pocket lined by residues Trp20, Phe122, and Trp219, with the bromo-fluorobenzyl group inside the "specificity" pocket. The interactions between Minalrestat's bromo-fluorobenzyl group and the enzyme include the stacking against the side-chain of Trp111 as well as hydrogen bonding distances with residues Leu300 and Thr113. The carbamoyl group in Fidarestat formed a hydrogen bond with the main-chain nitrogen atom of Leu300. The atomic resolution refinement allowed the positioning of hydrogen atoms and accurate determination of bond lengths of the inhibitors, coenzyme NADP+ and active-site residue His110. The 1'-position nitrogen atom in the hydantoin and succinimide moieties of Fidarestat and Minalrestat, respectively, form a hydrogen bond with the Nepsilon2 atom of His 110. For Fidarestat, the electron density indicated two possible positions for the H-atom in this bond. Furthermore, both native and anomalous difference maps indicated the replacement of a water molecule linked to His110 by a Cl-ion. These observations suggest a mechanism in which Fidarestat is bound protonated and becomes negatively charged by donating the proton to His110, which may have important implications on drug design.
-==About this Structure==
-PWL 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=1PWL OCA].
-==Reference==
-Ultrahigh resolution drug design. II. Atomic resolution structures of human aldose reductase holoenzyme complexed with Fidarestat and Minalrestat: implications for the binding of cyclic imide inhibitors., El-Kabbani O, Darmanin C, Schneider TR, Hazemann I, Ruiz F, Oka M, Joachimiak A, Schulze-Briese C, Tomizaki T, Mitschler A, Podjarny A, Proteins. 2004 Jun 1;55(4):805-13. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15146479 15146479]
-[[Category: Aldehyde reductase]]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Darmanin, C.]]
+[[Category: Darmanin C]]
-[[Category: El-Kabbani, O.]]
+[[Category: El-Kabbani O]]
-[[Category: Hazemann, I.]]
+[[Category: Hazemann I]]
-[[Category: Joachimiak, A.]]
+[[Category: Joachimiak A]]
-[[Category: Mitschler, A.]]
+[[Category: Mitschler A]]
-[[Category: Oka, M.]]
+[[Category: Oka M]]
-[[Category: Podjarny, A.]]
+[[Category: Podjarny A]]
-[[Category: Ruiz, F.]]
+[[Category: Ruiz F]]
-[[Category: Schneider, T R.]]
+[[Category: Schneider TR]]
-[[Category: Schulze-Briese, C.]]
+[[Category: Schulze-Briese C]]
-[[Category: Tomizaki, T.]]
+[[Category: Tomizaki T]]
-[[Category: aldose reductase]]
-[[Category: atomic resolution]]
-[[Category: inhibitor binding]]
-[[Category: ternary complex]]
-[[Category: x-ray crystallography]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:05:31 2008''

1pwl

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Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat

Structural highlights

Function

Evolutionary Conservation

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