Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1.
Gamma-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.
Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland.
Fang
F
Wu
Claude
C
Schweizer
Nikita
N
Rudinskiy
David M
DM
Taylor
Aleksey
A
Kazantsev
Ruth
R
Luthi-Carter
Patrick C
PC
Fraering
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D053616:Janus Kinase 3 / Q000737:chemistry*; D009281:Naphthalenes; D009711:Nucleotides / Q000378:metabolism*; D053764:Presenilin-1 / Q000737:chemistry*; D056565:Sirtuin 2 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D009711:Nucleotides; D053764:Presenilin-1; C062247:2-hydroxy-1-naphthaldehyde; D053616:Janus Kinase 3; D053829:Amyloid Precursor Protein Secretases; D056565:Sirtuin 2