Crystal Structure of Human ABAD/HSD10 with a Bound Inhibitor: Implications for Design of Alzheimerʹs Disease Therapeutics

The enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10), also known as amyloid β-peptide-binding alcohol dehydrogenase (ABAD), has been implicated in the development of Alzheimerʹs disease. This protein, a member of the short-chain dehydrogenase/reductase family of enzymes, has been shown to bind β-amyloid and to participate in β-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 Alzheimerʹs disease.