|
|
| (16 intermediate revisions by the same user not shown) |
| Line 1: |
Line 1: |
| [[Image:1lde.gif|left|200px]]<br /><applet load="1lde" size="350" color="white" frame="true" align="right" spinBox="true"
| |
| caption="1lde, resolution 2.5Å" />
| |
| '''HORSE LIVER ALCOHOL DEHYDROGENASE COMPLEXED TO NADH AND N-FORMYL PIPERDINE'''<br />
| |
|
| |
|
| ==Overview== | | ==HORSE LIVER ALCOHOL DEHYDROGENASE COMPLEXED TO NADH AND N-FORMYL PIPERDINE== |
| Amides are analogs of aldehydes and potent inhibitors of liver alcohol, dehydrogenases. They can be used for structural studies and for inhibiting, the metabolism of alcohols that form toxic products. We studied N-alkyl, amides that bind to the enzyme-NADH complex and act as uncompetitive, inhibitors against varied concentrations of ethanol (millimolar Kii, values, at pH 8 and 25 degrees C): N-propylacetamide (16), delta-valerolactam (1.6), N-formylpiperidine (0.14), N-isobutylformamide, (0.028), N-(cyclohexylmethyl)-formamide (0.011), and N-cyclohexylformamide, (0.0087). The lower affinity of delta-valerolactam and N-propylacetamide, can be explained by steric hindrance with Phe93 of the enzyme. Replacing, Phe93 with Ala in the S48T/F93A mutated enzyme, which resembles the, natural alpha-isoenzyme of primates, improved binding of, delta-valerolactam by 210-fold. The structures of horse liver enzyme, complexed with NADH and N-cyclohexylformamide or N-formylpiperidine were, determined by X-ray crystallography at 2.5 A resolution. In both, complexes, the carbonyl oxygens of the inhibitors bind to the catalytic, zinc and form a hydrogen bond to the hydroxyl group of Ser48 of the, enzyme. The six-membered rings bind in overlapping, but rotated, positions, that optimize hydrophobic interactions. The binding modes of the, unreactive formamides appear to resemble the Michaelis complexes of the, analogous substrates, with the re face of the carbonyl carbon suitably, positioned to accept a hydrogen from NADH.
| | <StructureSection load='1lde' size='340' side='right'caption='[[1lde]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == |
| | <table><tr><td colspan='2'>[[1lde]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Equus_caballus Equus caballus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LDE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LDE 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]] 2.5Å</td></tr> |
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FPI:N-FORMYLPIPERIDINE'>FPI</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=1lde FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lde OCA], [https://pdbe.org/1lde PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1lde RCSB], [https://www.ebi.ac.uk/pdbsum/1lde PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1lde ProSAT]</span></td></tr> |
| | </table> |
| | == Function == |
| | [https://www.uniprot.org/uniprot/ADH1E_HORSE ADH1E_HORSE] |
| | == 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/ld/1lde_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=1lde ConSurf]. |
| | <div style="clear:both"></div> |
|
| |
|
| ==About this Structure== | | ==See Also== |
| 1LDE is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Equus_caballus Equus caballus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=FPI:'>FPI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Alcohol_dehydrogenase Alcohol dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.1 1.1.1.1] Known structural/functional Site: <scene name='pdbsite=NAD:Nicotinamide-Adenine-Dinucleotide+Site'>NAD</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LDE OCA].
| | *[[Alcohol dehydrogenase 3D structures|Alcohol dehydrogenase 3D structures]] |
| | | __TOC__ |
| ==Reference==
| | </StructureSection> |
| Binding of formamides to liver alcohol dehydrogenase., Ramaswamy S, Scholze M, Plapp BV, Biochemistry. 1997 Mar 25;36(12):3522-7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9132002 9132002]
| |
| [[Category: Alcohol dehydrogenase]]
| |
| [[Category: Equus caballus]] | | [[Category: Equus caballus]] |
| [[Category: Single protein]] | | [[Category: Large Structures]] |
| [[Category: Plapp, B.V.]] | | [[Category: Plapp BV]] |
| [[Category: Ramaswamy, S.]] | | [[Category: Ramaswamy S]] |
| [[Category: FPI]]
| |
| [[Category: NAD]]
| |
| [[Category: ZN]]
| |
| [[Category: alcohol]]
| |
| [[Category: dehydrogenase]]
| |
| [[Category: formamides]]
| |
| [[Category: nicotinamide coenzyme]]
| |
| [[Category: oxidoreductase]]
| |
| | |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 09:53:13 2008''
| |