2acr

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(New page: 200px<br /> <applet load="2acr" size="450" color="white" frame="true" align="right" spinBox="true" caption="2acr, resolution 1.76&Aring;" /> '''AN ANION BINDING SI...)
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[[Image:2acr.gif|left|200px]]<br />
 
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<applet load="2acr" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2acr, resolution 1.76&Aring;" />
 
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'''AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE'''<br />
 
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==Overview==
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==AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE==
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Aldose reductase is a NADPH-dependent aldo-keto reductase involved in the, pathogenesis of some diabetic and galactosemic complications. The, published crystal structure of human aldose reductase [Wilson et al., (1992) Science 257, 81-84] contains a hitherto unexplained electron, density positioned within the active site pocket facing the nicotinamide, ring of the NADPH and other key active site residues (Tyr48, His110, and, Cys298). In this paper we identify the electron density as citrate, which, is present in the crystallization buffer (pH 5.0), and provide, confirmatory evidence by both kinetic and crystallographic experiments., Citrate is an uncompetitive inhibitor in the forward reaction with respect, to aldehyde (reduction of aldehyde), while it is a competitive inhibitor, with respect to alcohol in the backward reaction (oxidation of alcohol), indicating that it interacts with the enzyme-NADP(+)-product complex., Citrate can be replaced in the crystalline enzyme complex by cacodylate or, glucose 6-phosphate; the structure of each of these complexes shows the, specific molecule bound in the active site. All of the structures have, been determined to a nominal resolution of 1.76 A and refined to R-factors, below 18%. While cacodylate can be bound within the active site under the, crystallization conditions, it does not inhibit the wild-type enzyme in, solution. Glucose 6-phosphate, however, is a substrate for aldose, reductase. The similar location of the negative charges of citrate, cacodylate, and glucose 6-phosphate within the active site suggests an, anion-binding site delineated by the C4N of nicotinamide, the OH of Tyr48, and the N epsilon of His110. The location of citrate binding in the active, site leads to a plausible catalytic mechanism for aldose reductase.
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<StructureSection load='2acr' size='340' side='right'caption='[[2acr]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2acr]] 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=2ACR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ACR 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]] 1.76&#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=CAC:CACODYLATE+ION'>CAC</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=2acr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2acr OCA], [https://pdbe.org/2acr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2acr RCSB], [https://www.ebi.ac.uk/pdbsum/2acr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2acr 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/ac/2acr_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=2acr 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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2ACR 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 CAC and NAP 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2ACR 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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An anion binding site in human aldose reductase: mechanistic implications for the binding of citrate, cacodylate, and glucose 6-phosphate., Harrison DH, Bohren KM, Ringe D, Petsko GA, Gabbay KH, Biochemistry. 1994 Mar 1;33(8):2011-20. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8117658 8117658]
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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: Bohren, K.M.]]
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[[Category: Bohren KM]]
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[[Category: Gabbay, K.H.]]
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[[Category: Gabbay KH]]
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[[Category: Harrison, D.H.]]
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[[Category: Harrison DH]]
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[[Category: Petsko, G.A.]]
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[[Category: Petsko GA]]
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[[Category: Ringe, D.]]
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[[Category: Ringe D]]
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[[Category: CAC]]
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[[Category: NAP]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:48:59 2007''
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Current revision

AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE

PDB ID 2acr

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