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New page: left|200px<br /> <applet load="2agt" size="450" color="white" frame="true" align="right" spinBox="true" caption="2agt, resolution 1.00Å" /> '''Aldose Reductase Mu... |
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== | ==Aldose Reductase Mutant Leu 300 Pro complexed with Fidarestat== | ||
Structure of the Leu300Pro mutant of human aldose reductase (ALR2) in | <StructureSection load='2agt' size='340' side='right'caption='[[2agt]], [[Resolution|resolution]] 1.00Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2agt]] 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=2AGT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AGT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FID:(2S,4S)-2-AMINOFORMYL-6-FLUORO-SPIRO[CHROMAN-4,4-IMIDAZOLIDINE]-2,5-DIONE'>FID</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2agt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2agt OCA], [https://pdbe.org/2agt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2agt RCSB], [https://www.ebi.ac.uk/pdbsum/2agt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2agt ProSAT]</span></td></tr> | |||
</table> | |||
== 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/ag/2agt_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=2agt ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Structure of the Leu300Pro mutant of human aldose reductase (ALR2) in complex with the inhibitor fidarestat is determined. Comparison with the hALR2-fidarestat complex and the porcine aldehyde reductase (ALR1)-fidarestat complex indicates that the hydrogen bond between the Leu300 amino group of the wild-type and the exocyclic amide group of the inhibitor is the key determinant for the specificity of fidarestat for ALR2 over ALR1. Thermodynamic data also suggest an enthalpic contribution as the predominant difference in the binding energy between the aldose reductase mutant and the wild-type. An additional selectivity-determining feature is the difference in the interaction between the inhibitor and the side chain of Trp219, ordered in the present structure but disordered (corresponding Trp220) in the ALR1-fidarestat complex. Thus, the hydrogen bond ( approximately 7 kJ/mol) corresponds to a 23-fold difference in inhibitor potency while the differences in the interactions between Trp219(ALR2) and fidarestat and between Trp220(ALR1) and fidarestat can account for an additional 10-fold difference in potency. | |||
Factorizing selectivity determinants of inhibitor binding toward aldose and aldehyde reductases: structural and thermodynamic properties of the aldose reductase mutant Leu300Pro-fidarestat complex.,Petrova T, Steuber H, Hazemann I, Cousido-Siah A, Mitschler A, Chung R, Oka M, Klebe G, El-Kabbani O, Joachimiak A, Podjarny A J Med Chem. 2005 Sep 8;48(18):5659-65. PMID:16134934<ref>PMID:16134934</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[ | <div class="pdbe-citations 2agt" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Aldose reductase 3D structures|Aldose reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Chung | [[Category: Chung R]] | ||
[[Category: Cousido-Siah | [[Category: Cousido-Siah A]] | ||
[[Category: El-Kabbani | [[Category: El-Kabbani O]] | ||
[[Category: Hazemann | [[Category: Hazemann I]] | ||
[[Category: Joachimiak | [[Category: Joachimiak A]] | ||
[[Category: Klebe | [[Category: Klebe G]] | ||
[[Category: Mitschler | [[Category: Mitschler A]] | ||
[[Category: Oka | [[Category: Oka M]] | ||
[[Category: Petrova | [[Category: Petrova T]] | ||
[[Category: Podjarny | [[Category: Podjarny A]] | ||
[[Category: Steuber | [[Category: Steuber H]] | ||
Latest revision as of 10:24, 23 August 2023
Aldose Reductase Mutant Leu 300 Pro complexed with FidarestatAldose Reductase Mutant Leu 300 Pro complexed with Fidarestat
Structural highlights
FunctionALDR_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 Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedStructure of the Leu300Pro mutant of human aldose reductase (ALR2) in complex with the inhibitor fidarestat is determined. Comparison with the hALR2-fidarestat complex and the porcine aldehyde reductase (ALR1)-fidarestat complex indicates that the hydrogen bond between the Leu300 amino group of the wild-type and the exocyclic amide group of the inhibitor is the key determinant for the specificity of fidarestat for ALR2 over ALR1. Thermodynamic data also suggest an enthalpic contribution as the predominant difference in the binding energy between the aldose reductase mutant and the wild-type. An additional selectivity-determining feature is the difference in the interaction between the inhibitor and the side chain of Trp219, ordered in the present structure but disordered (corresponding Trp220) in the ALR1-fidarestat complex. Thus, the hydrogen bond ( approximately 7 kJ/mol) corresponds to a 23-fold difference in inhibitor potency while the differences in the interactions between Trp219(ALR2) and fidarestat and between Trp220(ALR1) and fidarestat can account for an additional 10-fold difference in potency. Factorizing selectivity determinants of inhibitor binding toward aldose and aldehyde reductases: structural and thermodynamic properties of the aldose reductase mutant Leu300Pro-fidarestat complex.,Petrova T, Steuber H, Hazemann I, Cousido-Siah A, Mitschler A, Chung R, Oka M, Klebe G, El-Kabbani O, Joachimiak A, Podjarny A J Med Chem. 2005 Sep 8;48(18):5659-65. PMID:16134934[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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