1v1r

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(New page: 200px<br /> <applet load="1v1r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1v1r, resolution 1.80&Aring;" /> '''CROSSTALK BETWEEN C...)
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[[Image:1v1r.gif|left|200px]]<br />
 
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<applet load="1v1r" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1v1r, resolution 1.80&Aring;" />
 
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'''CROSSTALK BETWEEN COFACTOR BINDING AND THE PHOSPHORYLATION LOOP CONFORMATION IN THE BCKD MACHINE'''<br />
 
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==Overview==
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==CROSSTALK BETWEEN COFACTOR BINDING AND THE PHOSPHORYLATION LOOP CONFORMATION IN THE BCKD MACHINE==
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The decarboxylase/dehydrogenase (E1b) component of the 4-megadalton human, branched-chain alpha-keto acid dehydrogenase (BCKD) metabolic machine is a, thiamin diphosphate (ThDP)-dependent enzyme with a heterotetrameric, cofactor-binding fold. The E1b component catalyzes the decarboxylation of, alpha-keto acids and the subsequent reductive acylation of the lipoic, acid-bearing domain (LBD) from the 24-meric transacylase (E2b) core. In, the present study, we show that the binding of cofactor ThDP to the E1b, active site induces a disorder-to-order transition of the conserved, phosphorylation loop carrying the two phosphorylation sites Ser(292)-alpha, and Ser(302)-alpha, as deduced from the 1.80-1.85 A apoE1b and holoE1b, structures. The induced loop conformation is essential for the ... [[http://ispc.weizmann.ac.il/pmbin/getpm?15166214 (full description)]]
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<StructureSection load='1v1r' size='340' side='right'caption='[[1v1r]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1v1r]] is a 2 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=1V1R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1V1R 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]] 1.8&#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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1v1r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1v1r OCA], [https://pdbe.org/1v1r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1v1r RCSB], [https://www.ebi.ac.uk/pdbsum/1v1r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1v1r ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:[https://omim.org/entry/248600 248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:2060625</ref> <ref>PMID:8037208</ref> <ref>PMID:2703538</ref> <ref>PMID:2241958</ref> <ref>PMID:1867199</ref> <ref>PMID:1885764</ref> <ref>PMID:8161368</ref> <ref>PMID:7883996</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).
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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/v1/1v1r_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1v1r 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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The decarboxylase/dehydrogenase (E1b) component of the 4-megadalton human branched-chain alpha-keto acid dehydrogenase (BCKD) metabolic machine is a thiamin diphosphate (ThDP)-dependent enzyme with a heterotetrameric cofactor-binding fold. The E1b component catalyzes the decarboxylation of alpha-keto acids and the subsequent reductive acylation of the lipoic acid-bearing domain (LBD) from the 24-meric transacylase (E2b) core. In the present study, we show that the binding of cofactor ThDP to the E1b active site induces a disorder-to-order transition of the conserved phosphorylation loop carrying the two phosphorylation sites Ser(292)-alpha and Ser(302)-alpha, as deduced from the 1.80-1.85 A apoE1b and holoE1b structures. The induced loop conformation is essential for the recognition of lipoylated LBD to initiate E1b-catalyzed reductive acylation. Alterations of invariant Arg(287)-alpha, Asp(295)-alpha, Tyr(300)-alpha, and Arg(301)-alpha that form a hydrogen-bonding network in the phosphorylation loop result in the disordering of the loop conformation as elucidated by limited proteolysis, accompanied by the impaired binding and diminished reductive acylation of lipoylated LBD. In contrast, k(cat) values for E1b-catalyzed decarboxylation of the alpha-keto acid are higher in these E1b mutants than in wild-type E1b, with higher K(m) values for the substrate in the mutants. ThDP binding that orders the loop prevents phosphorylation of E1b by the BCKD kinase and averts the inactivation of wild-type E1b, but not the above mutants, by this covalent modification. Our results establish that the cross-talk between the bound ThDP and the phosphorylation loop conformation serves as a feed-forward switch for multiple reaction steps in the BCKD metabolic machine.
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==About this Structure==
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Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase.,Li J, Wynn RM, Machius M, Chuang JL, Karthikeyan S, Tomchick DR, Chuang DT J Biol Chem. 2004 Jul 30;279(31):32968-78. Epub 2004 May 27. PMID:15166214<ref>PMID:15166214</ref>
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1V1R is a [[http://en.wikipedia.org/wiki/Protein_complex Protein complex]] structure of sequences from [[http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]] with CL, K, NA, SO4 and GOL as [[http://en.wikipedia.org/wiki/ligands ligands]]. Active as [[http://en.wikipedia.org/wiki/ ]], with EC number [[http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4]]. Full crystallographic information is available from [[http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1V1R 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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Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase., Li J, Wynn RM, Machius M, Chuang JL, Karthikeyan S, Tomchick DR, Chuang DT, J Biol Chem. 2004 Jul 30;279(31):32968-78. Epub 2004 May 27. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15166214 15166214]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1v1r" style="background-color:#fffaf0;"></div>
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[[Category: Protein complex]]
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[[Category: Chuang, D.T.]]
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[[Category: Chuang, J.L.]]
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[[Category: Karthikeyan, S.]]
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[[Category: Li, J.]]
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[[Category: Machius, M.]]
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[[Category: Tomchick, D.R.]]
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[[Category: Wynn, R.M.]]
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[[Category: CL]]
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[[Category: GOL]]
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[[Category: K]]
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[[Category: NA]]
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[[Category: SO4]]
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[[Category: acylation]]
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[[Category: branched-chain]]
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[[Category: flavoprotein]]
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[[Category: ketoacid dehydrogenase]]
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[[Category: multi-enzyme complex]]
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[[Category: oxidative decarboxylation maple syrup urine disease]]
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[[Category: oxidoreductase]]
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[[Category: phosphorylation]]
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[[Category: thiamin diphosphate]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Oct 29 19:29:58 2007''
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==See Also==
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*[[2-oxoisovalerate dehydrogenase 3D structures|2-oxoisovalerate dehydrogenase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Chuang DT]]
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[[Category: Chuang JL]]
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[[Category: Karthikeyan S]]
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[[Category: Li J]]
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[[Category: Machius M]]
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[[Category: Tomchick DR]]
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[[Category: Wynn RM]]

Current revision

CROSSTALK BETWEEN COFACTOR BINDING AND THE PHOSPHORYLATION LOOP CONFORMATION IN THE BCKD MACHINE

PDB ID 1v1r

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