Abstract
The enzyme 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), also known as amyloid beta-peptide-binding alcohol dehydrogenase (ABAD), has been implicated in the development of Alzheimer's disease. This protein, a member of the short-chain dehydrogenase/reductase family of enzymes, has been shown to bind beta-amyloid and to participate in beta-amyloid neurotoxicity. We have determined the crystal structure of human ABAD/HSD10 complexed with NAD(+) and an inhibitory small molecule. The inhibitor occupies the substrate-binding site and forms a covalent adduct with the NAD(+) cofactor. The crystal structure provides a basis for the design of potent, highly specific ABAD/HSD10 inhibitors with potential application in the treatment of Alzheimer's disease.
MeSH terms
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3-Hydroxyacyl CoA Dehydrogenases / antagonists & inhibitors*
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3-Hydroxyacyl CoA Dehydrogenases / chemistry*
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3-Hydroxyacyl CoA Dehydrogenases / genetics
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3-Hydroxyacyl CoA Dehydrogenases / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / enzymology*
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Amino Acid Sequence
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Amyloid beta-Peptides / metabolism
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Base Sequence
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Catalytic Domain
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Crystallography, X-Ray
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DNA, Complementary / genetics
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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In Vitro Techniques
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Kinetics
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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NAD / chemistry
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Protein Conformation
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Protein Structure, Quaternary
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
Substances
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Amyloid beta-Peptides
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DNA, Complementary
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Enzyme Inhibitors
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Recombinant Proteins
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NAD
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3-Hydroxyacyl CoA Dehydrogenases
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HSD17B10 protein, human