2bew

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[[Image:2bew.gif|left|200px]]<br /><applet load="2bew" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2bew, resolution 1.79&Aring;" />
 
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'''REACTIVITY MODULATION OF HUMAN BRANCHED-CHAIN ALPHA-KETOACID DEHYDROGENASE BY AN INTERNAL MOLECULAR SWITCH'''<br />
 
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==Overview==
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==Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch==
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The dehydrogenase/decarboxylase (E1b) component of the 4 MD human, branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin, diphosphate (ThDP)-dependent enzyme. We have determined the crystal, structures of E1b with ThDP bound intermediates after decarboxylation of, alpha-ketoacids. We show that a key tyrosine residue in the E1b active, site functions as a conformational switch to reduce the reactivity of the, ThDP cofactor through interactions with its thiazolium ring. The, intermediates do not assume the often-postulated enamine state, but likely, a carbanion state. The carbanion presumably facilitates the second, E1b-catalyzed reaction, involving the transfer of an acyl moiety from the, intermediate to a lipoic acid prosthetic group in the transacylase (E2b), component of the BCKDC. The tyrosine switch further remodels an E1b loop, region to promote E1b binding to E2b. Our results illustrate the, versatility of the tyrosine switch in coordinating the catalytic events in, E1b by modulating the reactivity of reaction intermediates.
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<StructureSection load='2bew' size='340' side='right'caption='[[2bew]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2bew]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BEW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BEW 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]] 1.79&#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=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=THW:C2-1-HYDROXYPHENYL-THIAMIN+DIPHOSPHATE'>THW</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=2bew FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bew OCA], [https://pdbe.org/2bew PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bew RCSB], [https://www.ebi.ac.uk/pdbsum/2bew PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bew ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_HUMAN] Defects in BCKDHB are the cause of maple syrup urine disease type IB (MSUD1B) [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:8161368</ref> <ref>PMID:11509994</ref> <ref>PMID:22326532</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_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/be/2bew_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=2bew 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 dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates.
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==Disease==
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A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase.,Machius M, Wynn RM, Chuang JL, Li J, Kluger R, Yu D, Tomchick DR, Brautigam CA, Chuang DT Structure. 2006 Feb;14(2):287-98. PMID:16472748<ref>PMID:16472748</ref>
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Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348 608348]], Maple syrup urine disease, type Ib OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248611 248611]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2BEW 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 <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=THW:'>THW</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3-methyl-2-oxobutanoate_dehydrogenase_(2-methylpropanoyl-transferring) 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4] Known structural/functional Site: <scene name='pdbsite=AC1:Gol+Binding+Site+For+Chain+B'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BEW OCA].
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</div>
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<div class="pdbe-citations 2bew" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase., Machius M, Wynn RM, Chuang JL, Li J, Kluger R, Yu D, Tomchick DR, Brautigam CA, Chuang DT, Structure. 2006 Feb;14(2):287-98. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16472748 16472748]
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*[[2-oxoisovalerate dehydrogenase 3D structures|2-oxoisovalerate dehydrogenase 3D structures]]
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[[Category: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Brautigam, C.A.]]
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[[Category: Synthetic construct]]
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[[Category: Chuang, D.T.]]
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[[Category: Brautigam CA]]
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[[Category: Chuang, J.L.]]
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[[Category: Chuang DT]]
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[[Category: Machius, M.]]
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[[Category: Chuang JL]]
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[[Category: Tomchick, D.R.]]
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[[Category: Machius M]]
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[[Category: Wynn, R.M.]]
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[[Category: Tomchick DR]]
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[[Category: CL]]
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[[Category: Wynn RM]]
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[[Category: GOL]]
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[[Category: K]]
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[[Category: MN]]
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[[Category: THW]]
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[[Category: acylation]]
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[[Category: branched-chain]]
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[[Category: conformational switch]]
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[[Category: ketoacid dehydrogenase]]
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[[Category: maple syrup urine disease]]
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[[Category: multi-enzyme complex]]
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[[Category: oxidative decarboxylation]]
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[[Category: oxidoreductase]]
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[[Category: phosphorylation]]
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[[Category: reactivity]]
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[[Category: thiamine diphosphate]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 10:23:14 2008''
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Current revision

Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch

PDB ID 2bew

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