Academic Journal
Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1.
| العنوان: | Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1. |
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| المؤلفون: | Wu, F, Schweizer, C, Rudinskiy, N, Taylor, DM, Kazantsev, A, Luthi-Carter, R, Fraering, PC |
| المصدر: | PubMed ; http://www.ncbi.nlm.nih.gov/pubmed/ |
| سنة النشر: | 2012 |
| المجموعة: | University of Leicester: Leicester Research Archive (LRA) |
| مصطلحات موضوعية: | Amyloid Precursor Protein Secretases, Binding Sites, Drug Discovery, Enzyme Inhibitors, Humans, Janus Kinase 3, Naphthalenes, Nucleotides, Presenilin-1, Sirtuin 2, Structure-Activity Relationship, Substrate Specificity |
| الوصف: | 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. ; 103454 |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | metadata |
| اللغة: | English |
| تدمد: | 1530-6860 |
| Relation: | FASEB J, 2010, 24 (7), pp. 2464-2474; http://hdl.handle.net/2381/11648; fj.09-148031 |
| DOI: | 10.1096/fj.09-148031 |
| الاتاحة: | http://hdl.handle.net/2381/11648 https://doi.org/10.1096/fj.09-148031 |
| رقم الانضمام: | edsbas.DDD7AFD |
| قاعدة البيانات: | BASE |
| تدمد: | 15306860 |
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| DOI: | 10.1096/fj.09-148031 |