2r0n

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{{STRUCTURE_2r0n| PDB=2r0n | SCENE= }}
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==The effect of a Glu370Asp mutation in Glutaryl-CoA Dehydrogenase on Proton Transfer to the Dienolate Intermediate==
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===The effect of a Glu370Asp mutation in Glutaryl-CoA Dehydrogenase on Proton Transfer to the Dienolate Intermediate===
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<StructureSection load='2r0n' size='340' side='right' caption='[[2r0n]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_18020372}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2r0n]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R0N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2R0N FirstGlance]. <br>
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==Disease==
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=TGC:3-THIAGLUTARYL-COA'>TGC</scene><br>
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[[http://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN]] Defects in GCDH are the cause of glutaric aciduria type 1 (GA1) [MIM:[http://omim.org/entry/231670 231670]]. GA1 is an autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia.<ref>PMID:18775954</ref><ref>PMID:8541831</ref><ref>PMID:9600243</ref><ref>PMID:8900227</ref><ref>PMID:8900228</ref><ref>PMID:14707522</ref>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r0m|2r0m]]</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenase Glutaryl-CoA dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.99.7 1.3.99.7] </span></td></tr>
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==Function==
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2r0n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r0n OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2r0n RCSB], [http://www.ebi.ac.uk/pdbsum/2r0n PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN]] Defects in GCDH are the cause of glutaric aciduria type 1 (GA1) [MIM:[http://omim.org/entry/231670 231670]]. GA1 is an autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia.<ref>PMID:18775954</ref> <ref>PMID:8541831</ref> <ref>PMID:9600243</ref> <ref>PMID:8900227</ref> <ref>PMID:8900228</ref> <ref>PMID:14707522</ref>
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== Function ==
[[http://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN]] Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.
[[http://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN]] Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.
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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/r0/2r0n_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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We have determined steady-state rate constants and net rate constants for the chemical steps in the catalytic pathway catalyzed by the E370D mutant of glutaryl-CoA dehydrogenase and compared them with those of the wild-type dehydrogenase. We sought rationales for changes in these rate constants in the structure of the mutant cocrystallized with the alternate substrate, 4-nitrobutyric acid. Substitution of aspartate for E370, the catalytic base, results in a 24% decrease in the rate constant for proton abstraction at C-2 of 3-thiaglutaryl-CoA as the distance between C-2 of the ligand and the closest carboxyl oxygen at residue 370 increases from 2.9 A to 3.1 A. The net rate constant for flavin reduction due to hydride transfer from C-3 of the natural substrate, which includes proton abstraction at C-2, to N5 of the flavin decreases by 81% due to the mutation, although the distance increases only by 0.7 A. The intensities of charge-transfer bands associated with the enolate of 3-thiaglutaryl-CoA, the reductive half-reaction (reduced flavin with oxidized form of substrate), and the dienolate following decarboxylation are considerably diminished. Structural investigation suggests that the increased distance and the change in angle of the S-C1(=O)-C2 plane of the substrate with the isoalloxazine substantially alter rates of the reductive and oxidative half-reactions. This change in active site geometry also changes the position of protonation of the four carbon dienolate intermediate to produce kinetically favorable product, vinylacetyl-CoA, which is further isomerized to the thermodynamically stable normal product, crotonyl-CoA.
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==About this Structure==
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The effect of a Glu370Asp mutation in glutaryl-CoA dehydrogenase on proton transfer to the dienolate intermediate.,Rao KS, Fu Z, Albro M, Narayanan B, Baddam S, Lee HJ, Kim JJ, Frerman FE Biochemistry. 2007 Dec 18;46(50):14468-77. Epub 2007 Nov 17. PMID:18020372<ref>PMID:18020372</ref>
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[[2r0n]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R0N OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<ref group="xtra">PMID:018020372</ref><references group="xtra"/><references/>
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</div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Glutaryl-CoA dehydrogenase]]
[[Category: Glutaryl-CoA dehydrogenase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]

Revision as of 19:02, 30 September 2014

The effect of a Glu370Asp mutation in Glutaryl-CoA Dehydrogenase on Proton Transfer to the Dienolate Intermediate

2r0n, resolution 2.30Å

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