View source for 2pdh


==Human aldose reductase mutant L300P complexed with uracil-type inhibitor at 1.45 A.==
<StructureSection load='2pdh' size='340' side='right'caption='[[2pdh]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2pdh]] 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=2PDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PDH 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]] 1.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=47D:{3-[(5-CHLORO-1,3-BENZOTHIAZOL-2-YL)METHYL]-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL}ACETIC+ACID'>47D</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=2pdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pdh OCA], [https://pdbe.org/2pdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pdh RCSB], [https://www.ebi.ac.uk/pdbsum/2pdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pdh 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/pd/2pdh_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=2pdh ConSurf].
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== Publication Abstract from PubMed ==
Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The resulting mutational constructs of ALR2 (eight point mutations and one double mutant) were probed for their influence towards ligand selectivity by X-ray structure analysis of the corresponding complexes and isothermal titration calorimetry (ITC). The binding properties of these mutants were evaluated using a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393, sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations within the mutated binding site as an essential prerequisite for ligand accommodation related to the selectivity discrimination of the ligands. However, our study also highlights the limits of the present understanding of protein-ligand interactions. Interestingly, binding site mutations not involved in any direct interaction to the ligands in various cases show significant effects towards their binding thermodynamics. Furthermore, our results suggest the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding.

Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.,Steuber H, Heine A, Podjarny A, Klebe G J Mol Biol. 2008 Jun 20;379(5):991-1016. Epub 2008 Apr 8. PMID:18495158<ref>PMID:18495158</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2pdh" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aldose reductase 3D structures|Aldose reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Heine A]]
[[Category: Klebe G]]
[[Category: Steuber H]]