5j5z

Crystal structure of the D444V disease-causing mutant of the human dihydrolipoamide dehydrogenase

spinqualitylabelsall models 5j5z, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5j5z is a 2 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 1.84Å Ligands: FAD, GOL, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DLDH_HUMAN Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. Function DLDH_HUMAN Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. Publication Abstract from PubMed We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84A resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme. Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase.,Szabo E, Mizsei R, Wilk P, Zambo Z, Torocsik B, Weiss MS, Adam-Vizi V, Ambrus A Free Radic Biol Med. 2018 Jun 20;124:214-220. doi:, 10.1016/j.freeradbiomed.2018.06.008. PMID:29908278 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrolipoamide dehydrogenase

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