1z3n

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(New page: 200px<br /> <applet load="1z3n" size="450" color="white" frame="true" align="right" spinBox="true" caption="1z3n, resolution 1.04&Aring;" /> '''Human aldose reduct...)
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[[Image:1z3n.gif|left|200px]]<br />
 
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<applet load="1z3n" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1z3n, resolution 1.04&Aring;" />
 
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'''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''<br />
 
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==Overview==
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==Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom==
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Recent efforts to identify treatments for chronic diabetic complications, have resulted in the discovery of a novel series of highly potent and, selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose, reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid, (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while, being 5400 times less active against aldehyde reductase, a related enzyme, involved in the detoxification of reactive aldehydes. It lowers nerve and, lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month, diabetic intervention model (1 month of diabetes followed by 2 months of, drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the, motor nerve conduction velocity deficit by 59% relative to diabetic, controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6, h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in, sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when, dosed with [(14)C]lidorestat at 10 mg/kg po).
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<StructureSection load='1z3n' size='340' side='right'caption='[[1z3n]], [[Resolution|resolution]] 1.04&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1z3n]] 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=1Z3N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Z3N 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]] 1.04&#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=3NA:{3-[(4,5,7-TRIFLUORO-1,3-BENZOTHIAZOL-2-YL)METHYL]-1H-INDOL-1-YL}ACETIC+ACID'>3NA</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=1z3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z3n OCA], [https://pdbe.org/1z3n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1z3n RCSB], [https://www.ebi.ac.uk/pdbsum/1z3n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1z3n 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/z3/1z3n_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=1z3n 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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1Z3N 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 NDP and 3NA 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=1Z3N 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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Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications., Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD, J Med Chem. 2005 May 5;48(9):3141-52. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15857120 15857120]
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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: Dicioccio, A.T.]]
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[[Category: Dicioccio AT]]
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[[Category: Geraci, L.S.]]
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[[Category: Geraci LS]]
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[[Category: Gunn, D.E.]]
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[[Category: Gunn DE]]
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[[Category: Jacot, J.L.]]
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[[Category: Jacot JL]]
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[[Category: Jones, J.H.]]
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[[Category: Jones JH]]
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[[Category: Jones, M.L.]]
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[[Category: Jones ML]]
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[[Category: Mitschler, A.]]
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[[Category: Mitschler A]]
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[[Category: Petrova, T.]]
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[[Category: Petrova T]]
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[[Category: Podjarny, A.D.]]
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[[Category: Podjarny AD]]
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[[Category: Sawicki, D.R.]]
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[[Category: Sawicki DR]]
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[[Category: Sredy, J.]]
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[[Category: Sredy J]]
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[[Category: Zandt, M.C.Van.]]
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[[Category: Van Zandt MC]]
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[[Category: 3NA]]
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[[Category: NDP]]
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[[Category: lidorestat]]
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[[Category: nadp+]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:28:53 2007''
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Current revision

Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom

PDB ID 1z3n

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