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| [[Image:1cw3.gif|left|200px]]<br />
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| <applet load="1cw3" size="450" color="white" frame="true" align="right" spinBox="true"
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| caption="1cw3, resolution 2.58Å" />
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| '''HUMAN MITOCHONDRIAL ALDEHYDE DEHYDROGENASE COMPLEXED WITH NAD+ AND MN2+'''<br />
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| ==Overview== | | ==HUMAN MITOCHONDRIAL ALDEHYDE DEHYDROGENASE COMPLEXED WITH NAD+ AND MN2+== |
| Human liver cytosolic and mitochondrial isozymes of aldehyde dehydrogenase, share 70% sequence identity. However, the first 21 residues are not, conserved between the human isozymes (15% identity). The three-dimensional, structures of the beef mitochondrial and sheep cytosolic forms have, virtually identical three-dimensional structures. Here, we solved the, structure of the human mitochondrial enzyme and found it to be identical, to the beef enzyme. The first 21 residues are found on the surface of the, enzyme and make no contact with other subunits in the tetramer. A pair of, chimeric enzymes between the human isozymes was made. Each chimera had the, first 21 residues from one isozyme and the remaining 479 from the other., When the first 21 residues were from the mitochondrial isozyme, an enzyme, with cytosolic-like properties was produced. The other was expressed but, was insoluble. It was possible to restore solubility and activity to the, chimera that had the first 21 cytosolic residues fused to the, mitochondrial ones by making point mutations to residues at the N-terminal, end. When residue 19 was changed from tyrosine to a cysteine, the residue, found in the mitochondrial form, an active enzyme could be made though the, Km for NAD+ was 35 times higher than the native mitochondrial isozyme and, the specific activity was reduced by 75%. This residue interacts with, residue 203, a nonconserved, nonactive site residue. A mutation of residue, 18, which also interacts with 203, restored solubility, but not activity., Mutation to residue 15, which interacts with 104, also restored solubility, but not activity. It appears that to have a soluble or active enzyme a, favorable interaction must occur between a residue in a surface loop and a, residue elsewhere in the molecule even though neither make contact with, the active site region of the enzyme.
| | <StructureSection load='1cw3' size='340' side='right'caption='[[1cw3]], [[Resolution|resolution]] 2.58Å' scene=''> |
| | == Structural highlights == |
| | <table><tr><td colspan='2'>[[1cw3]] is a 8 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=1CW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CW3 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]] 2.58Å</td></tr> |
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=1cw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1cw3 OCA], [https://pdbe.org/1cw3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1cw3 RCSB], [https://www.ebi.ac.uk/pdbsum/1cw3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1cw3 ProSAT]</span></td></tr> |
| | </table> |
| | == Function == |
| | [https://www.uniprot.org/uniprot/ALDH2_HUMAN ALDH2_HUMAN] |
| | == 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/cw/1cw3_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=1cw3 ConSurf]. |
| | <div style="clear:both"></div> |
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| ==Disease== | | ==See Also== |
| Known diseases associated with this structure: Alcohol intolerance, acute OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100650 100650]], Fetal alcohol syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100650 100650]]
| | *[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]] |
| | | __TOC__ |
| ==About this Structure==
| | </StructureSection> |
| 1CW3 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 MN, MG and NAD as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase_(NAD(+)) Aldehyde dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.3 1.2.1.3] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CW3 OCA].
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| ==Reference==
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| Human liver mitochondrial aldehyde dehydrogenase: three-dimensional structure and the restoration of solubility and activity of chimeric forms., Ni L, Zhou J, Hurley TD, Weiner H, Protein Sci. 1999 Dec;8(12):2784-90. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10631996 10631996]
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| [[Category: Aldehyde dehydrogenase (NAD(+))]]
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| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| [[Category: Single protein]] | | [[Category: Large Structures]] |
| [[Category: Hurley, T.D.]] | | [[Category: Hurley TD]] |
| [[Category: Ni, L.]] | | [[Category: Ni L]] |
| [[Category: Weiner, H.]] | | [[Category: Weiner H]] |
| [[Category: Zhou, J.]] | | [[Category: Zhou J]] |
| [[Category: MG]]
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| [[Category: MN]]
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| [[Category: NAD]]
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| [[Category: dinucleotide fold]]
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| ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:25:53 2007''
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