3mp5

Crystal Structure of Human Lyase R41M in complex with HMG-CoA

spinqualitylabelsall models 3mp5, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3mp5 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: HMG, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease HMGCL_HUMAN Defects in HMGCL are the cause of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM: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. Function HMGCL_HUMAN Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed HMG-CoA lyase (HMGCL) is crucial to ketogenesis, and inherited human mutations are potentially lethal. Detailed understanding of the HMGCL reaction mechanism and the molecular basis for correlating human mutations with enzyme deficiency have been limited by the lack of structural information for enzyme liganded to an acyl-CoA substrate or inhibitor. Crystal structures of ternary complexes of WT HMGCL with the competitive inhibitor 3-hydroxyglutaryl-CoA and of the catalytically deficient HMGCL R41M mutant with substrate HMG-CoA have been determined to 2.4 and 2.2 A, respectively. Comparison of these beta/alpha-barrel structures with those of unliganded HMGCL and R41M reveals substantial differences for Mg(2+) coordination and positioning of the flexible loop containing the conserved HMGCL "signature" sequence. In the R41M-Mg(2+)-substrate ternary complex, loop residue Cys(266) (implicated in active-site function by mechanistic and mutagenesis observations) is more closely juxtaposed to the catalytic site than in the case of unliganded enzyme or the WT enzyme-Mg(2+)-3-hydroxyglutaryl-CoA inhibitor complex. In both ternary complexes, the S-stereoisomer of substrate or inhibitor is specifically bound, in accord with the observed Mg(2+) liganding of both C3 hydroxyl and C5 carboxyl oxygens. In addition to His(233) and His(235) imidazoles, other Mg(2+) ligands are the Asp(42) carboxyl oxygen and an ordered water molecule. This water, positioned between Asp(42) and the C3 hydroxyl of bound substrate/inhibitor, may function as a proton shuttle. The observed interaction of Arg(41) with the acyl-CoA C1 carbonyl oxygen explains the effects of Arg(41) mutation on reaction product enolization and explains why human Arg(41) mutations cause drastic enzyme deficiency. Functional insights into human HMG-CoA lyase from structures of Acyl-CoA-containing ternary complexes.,Fu Z, Runquist JA, Montgomery C, Miziorko HM, Kim JJ J Biol Chem. 2010 Aug 20;285(34):26341-9. Epub 2010 Jun 17. PMID:20558737 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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