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dc.contributor.authorWu, F-
dc.contributor.authorSchweizer, C-
dc.contributor.authorRudinskiy, N-
dc.contributor.authorTaylor, DM-
dc.contributor.authorKazantsev, A-
dc.contributor.authorLuthi-Carter, R-
dc.contributor.authorFraering, PC-
dc.identifier.citationFASEB J, 2010, 24 (7), pp. 2464-2474-
dc.description.abstractGamma-secretase is an intramembrane-cleaving protease responsible for the final proteolytic event in the production of the amyloid-beta peptides (Abeta) implicated in Alzheimer's disease (AD). Inhibition of gamma-secretase activity is thus an attractive therapeutic strategy to slow down the pathogenesis of AD. Drugs often target more than one biomolecule because of conserved 3-dimensional structures in prospective protein binding sites. We have capitalized on this phenomenon of nature to identify new gamma-secretase inhibitors. Here we show that 2-hydroxy naphthyl derivatives, a previously identified subclass of NAD(+) analog inhibitors of sirtuin 2 (SIRT2), are direct gamma-secretase inhibitors. Subsequent structure-activity relationship studies further showed that 2-hydroxy-1-naphthaldehyde is the minimal pharmacophore for gamma-secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide-binding site (NBS) shared by the gamma-secretase subunit presenilin-1 C-terminal fragment (PS1-CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3-dimensional structure of gamma-secretase is beyond our knowledge, we took advantage of the known crystal structure of human JAK3 to model the NBS of the PS1-CTF, which includes the catalytic residue D385. Our results suggest that the flexible PS1-CTF (381)LGLG(384) loop comprises a substrate-docking site capable of recognizing specifically different gamma-secretase substrates.-
dc.subjectAmyloid Precursor Protein Secretases-
dc.subjectBinding Sites-
dc.subjectDrug Discovery-
dc.subjectEnzyme Inhibitors-
dc.subjectJanus Kinase 3-
dc.subjectSirtuin 2-
dc.subjectStructure-Activity Relationship-
dc.subjectSubstrate Specificity-
dc.titleNovel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1.-
dc.typeJournal Article-
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

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