2cw6
From Proteopedia
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| - | [[Image:2cw6.gif|left|200px]] | + | [[Image:2cw6.gif|left|200px]] |
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| - | '''Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria''' | + | {{Structure |
| + | |PDB= 2cw6 |SIZE=350|CAPTION= <scene name='initialview01'>2cw6</scene>, resolution 2.10Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> and <scene name='pdbligand=3HG:3-HYDROXYPENTANEDIOIC ACID'>3HG</scene> | ||
| + | |ACTIVITY= [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] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2CW6 is a [ | + | 2CW6 is a [[Single protein]] structure of 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=2CW6 OCA]. |
==Reference== | ==Reference== | ||
| - | 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:// | + | 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://www.ncbi.nlm.nih.gov/pubmed/16330550 16330550] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Hydroxymethylglutaryl-CoA lyase]] | [[Category: Hydroxymethylglutaryl-CoA lyase]] | ||
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[[Category: ketogenic enzyme]] | [[Category: ketogenic enzyme]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:20:29 2008'' |
Revision as of 14:20, 20 March 2008
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| , resolution 2.10Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Activity: | Hydroxymethylglutaryl-CoA lyase, with EC number 4.1.3.4 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria
Contents |
Overview
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.
Disease
Known disease associated with this structure: HMG-CoA lyase deficiency OMIM:[246450]
About this Structure
2CW6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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:16330550
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