title: Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.
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.
authors.affiliation: Pfizer-La Jolla, 10777 Science Center Dr., San Diego, CA 92121, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kissinger
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: Laura A
authors.initials: LA
authors.lastname: Pelletier
authors.forename: James A
authors.initials: JA
authors.lastname: Thomson
authors.forename: Richard E
authors.initials: RE
authors.lastname: Showalter
authors.forename: Melwyn A
authors.initials: MA
authors.lastname: Abreo
authors.forename: Charles S
authors.initials: CS
authors.lastname: Agree
authors.forename: Stephen
authors.initials: S
authors.lastname: Margosiak
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Meng
authors.forename: Robert M
authors.initials: RM
authors.lastname: Aust
authors.forename: Darin
authors.initials: D
authors.lastname: Vanderpool
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Anna
authors.initials: A
authors.lastname: Tempczyk-Russell
authors.forename: J Ernest
authors.initials: JE
authors.lastname: Villafranca
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001483:Base Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009243:NAD / Q000737:chemistry; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D009243:NAD; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human