2cw6

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(New page: 200px<br /> <applet load="2cw6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2cw6, resolution 2.10&Aring;" /> '''Crystal Structure o...)
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[[Image:2cw6.gif|left|200px]]<br />
 
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<applet load="2cw6" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2cw6, resolution 2.10&Aring;" />
 
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'''Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria'''<br />
 
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==Overview==
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==Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria==
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3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase is a key enzyme in the, ketogenic pathway that supplies metabolic fuel to extrahepatic tissues., Enzyme deficiency may be due to a variety of human mutations and can be, fatal. Diminished activity has been explained based on analyses of, recombinant human mutant proteins or, more recently, in the context of, structural models for the enzyme. We report the experimental determination, of a crystal structure at 2.1 A resolution of the recombinant human, mitochondrial HMG-CoA lyase containing a bound activator cation and the, dicarboxylic acid 3-hydroxyglutarate. The enzyme adopts a (betaalpha)(8), barrel fold, and the N-terminal barrel end is occluded. The structure of a, physiologically relevant dimer suggests that substrate access to the, active site involves binding across the cavity located at the C-terminal, end of the barrel. An alternative hypothesis that involves substrate, insertion through a pore proposed to extend through the barrel is not, compatible with the observed structure. The activator cation ligands, included Asn(275), Asp(42),His(233), and His(235); the latter three, residues had been implicated previously as contributing to metal binding, or enzyme activity. Arg(41), previously shown to have a major effect on, catalytic efficiency, is also located at the active site. In the observed, structure, this residue interacts with a carboxyl group of, 3-hydroxyglutarate, the hydrolysis product of the competitive inhibitor, 3-hydroxyglutaryl-CoA required for crystallization of human enzyme. The, structure provides a rationale for the decrease in enzyme activity due to, clinical mutations, including H233R, R41Q, D42H, and D204N, that, compromise active site function or enzyme stability.
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<StructureSection load='2cw6' size='340' side='right'caption='[[2cw6]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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==Disease==
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<table><tr><td colspan='2'>[[2cw6]] is a 6 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=2CW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CW6 FirstGlance]. <br>
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Known disease associated with this structure: HMG-CoA lyase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246450 246450]]
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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]] 2.1&#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=3HG:3-HYDROXYPENTANEDIOIC+ACID'>3HG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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==About this Structure==
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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=2cw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cw6 OCA], [https://pdbe.org/2cw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cw6 RCSB], [https://www.ebi.ac.uk/pdbsum/2cw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cw6 ProSAT]</span></td></tr>
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2CW6 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 MG and 3HG as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_lyase Hydroxymethylglutaryl-CoA lyase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.3.4 4.1.3.4] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CW6 OCA].
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</table>
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== Disease ==
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==Reference==
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[https://www.uniprot.org/uniprot/HMGCL_HUMAN HMGCL_HUMAN] Defects in HMGCL are the cause of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM:[https://omim.org/entry/246450 246450]; also known as hydroxymethylglutaricaciduria or HL deficiency. An autosomal recessive disease affecting ketogenesis and L-leucine catabolism. The disease usually appears in the first year of life after a fasting period and its clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and lethargy. These symptoms sometimes progress to coma, with fatal outcome in some cases.<ref>PMID:8798725</ref> <ref>PMID:9463337</ref> <ref>PMID:9784232</ref> <ref>PMID:11129331</ref> <ref>PMID:12746442</ref> <ref>PMID:17173698</ref> <ref>PMID:16601870</ref> <ref>PMID:17459752</ref> <ref>PMID:19036343</ref> <ref>PMID:19177531</ref>
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Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria., Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ, J Biol Chem. 2006 Mar 17;281(11):7526-32. Epub 2005 Dec 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16330550 16330550]
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== Function ==
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[https://www.uniprot.org/uniprot/HMGCL_HUMAN HMGCL_HUMAN] Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism.<ref>PMID:8566388</ref> <ref>PMID:22865860</ref> <ref>PMID:22847177</ref>
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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/cw/2cw6_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=2cw6 ConSurf].
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<div style="clear:both"></div>
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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: Hydroxymethylglutaryl-CoA lyase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Fu Z]]
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[[Category: Fu, Z.]]
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[[Category: Hunt JF]]
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[[Category: Hunt, J.F.]]
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[[Category: Kim J-JP]]
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[[Category: Kim, J.J.P.]]
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[[Category: Miziorko HM]]
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[[Category: Miziorko, H.M.]]
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[[Category: Runquist JA]]
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[[Category: Runquist, J.A.]]
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[[Category: 3HG]]
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[[Category: MG]]
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[[Category: hmg-coa lyase]]
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[[Category: ketogenic enzyme]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:24:25 2007''
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Current revision

Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria

PDB ID 2cw6

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