1w8d
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BINARY STRUCTURE OF HUMAN DECR.
OverviewOverview
Fatty acid catabolism by beta-oxidation mainly occurs in mitochondria and, to a lesser degree in peroxisomes. Poly-unsaturated fatty acids are, problematic for beta-oxidation, because the enzymes directly involved are, unable to process all the different double bond conformations and, combinations that occur naturally. In mammals, three accessory proteins, circumvent this problem by catalyzing specific isomerization and reduction, reactions. Central to this process is the NADPH-dependent 2,4-dienoyl-CoA, reductase. We present high resolution crystal structures of human, mitochondrial 2,4-dienoyl-CoA reductase in binary complex with cofactor, and the ternary complex with NADP(+) and substrate, trans-2,trans-4-dienoyl-CoA at 2.1 and 1.75 A resolution, respectively., The enzyme, a homotetramer, is a short-chain dehydrogenase/reductase with, a distinctive catalytic center. Close structural similarity between the, binary and ternary complexes suggests an absence of large conformational, changes during binding and processing of substrate. The site of catalysis, is relatively open and placed beside a flexible loop thereby allowing the, enzyme to accommodate and process a wide range of fatty acids. Seven, single mutants were constructed, by site-directed mutagenesis, to, investigate the function of selected residues in the active site thought, likely to either contribute to the architecture of the active site or to, catalysis. The mutant proteins were overexpressed, purified to, homogeneity, and then characterized. The structural and kinetic data are, consistent and support a mechanism that derives one reducing equivalent, from the cofactor, and one from solvent. Key to the acquisition of a, solvent-derived proton is the orientation of substrate and stabilization, of a dienolate intermediate by Tyr-199, Asn-148, and the oxidized, nicotinamide.
DiseaseDisease
Known diseases associated with this structure: DECR deficiency (2) OMIM:[222745]
About this StructureAbout this Structure
1W8D is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as 2,4-dienoyl-CoA reductase (NADPH), with EC number 1.3.1.34 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Structure and reactivity of human mitochondrial 2,4-dienoyl-CoA reductase: enzyme-ligand interactions in a distinctive short-chain reductase active site., Alphey MS, Yu W, Byres E, Li D, Hunter WN, J Biol Chem. 2005 Jan 28;280(4):3068-77. Epub 2004 Nov 6. PMID:15531764
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