2cw6

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spinqualitylabelsall models 2cw6, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 with MG and 3HG as ligands. Active as Hydroxymethylglutaryl-CoA lyase, with EC number 4.1.3.4 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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