View source for 1us0


==Human Aldose Reductase in complex with NADP+ and the inhibitor IDD594 at 0.66 Angstrom==
<StructureSection load='1us0' size='340' side='right'caption='[[1us0]], [[Resolution|resolution]] 0.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1us0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1US0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1US0 FirstGlance]. <br>
</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=LDT:IDD594'>LDT</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1abn|1abn]], [[1ads|1ads]], [[1az1|1az1]], [[1az2|1az2]], [[1ef3|1ef3]], [[1el3|1el3]], [[1iei|1iei]], [[1mar|1mar]], [[2acq|2acq]], [[2acr|2acr]], [[2acs|2acs]], [[2acu|2acu]]</div></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </span></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=1us0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1us0 OCA], [https://pdbe.org/1us0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1us0 RCSB], [https://www.ebi.ac.uk/pdbsum/1us0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1us0 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/us/1us0_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=1us0 ConSurf].
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== Publication Abstract from PubMed ==
The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (&lt;0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.

Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.,Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D, Schneider TR, Joachimiak A, Podjarny A Proteins. 2004 Jun 1;55(4):792-804. PMID:15146478<ref>PMID:15146478</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 1us0" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aldose reductase 3D structures|Aldose reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Aldehyde reductase]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Barth, P]]
[[Category: Bon, C]]
[[Category: Cachau, R E]]
[[Category: Chevrier, B]]
[[Category: Howard, E I]]
[[Category: Joachimiak, A]]
[[Category: Lamour, V]]
[[Category: Mitschler, A]]
[[Category: Moras, D]]
[[Category: Podjarny, A]]
[[Category: Sanishvili, R]]
[[Category: Schneider, T R]]
[[Category: Sibley, E]]
[[Category: Zandt, M Van]]
[[Category: Idd594]]
[[Category: Nadp]]
[[Category: Oxidoreductase]]