Modulation of γ-secretase specificity using small molecule allosteric inhibitors
| Autor: | Christopher C. Shelton, Deming Chau, Lei Zhu, Li Yang, Yue-Ming Li, Hakim Djaballah, Rong Wang, Hui Zheng |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Protein Conformation
Allosteric regulation Photoaffinity Labels Presenilin Substrate Specificity Small Molecule Libraries Notch Family Alzheimer Disease Coumarins Drug Discovery Chemical specificity Amyloid precursor protein Humans Amyloid beta-Peptides Multidisciplinary biology Chemistry Drug discovery Presenilins Biological Sciences Small molecule Kinetics Biochemistry Mutation biology.protein Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:20228-20233 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0910757106 |
| Popis: | gamma-Secretase cleaves multiple substrates within the transmembrane domain that include the amyloid precursor protein as well as the Notch family of receptors. These substrates are associated with Alzheimer disease and cancer. Despite extensive investigation of this protease, little is known regarding the regulation of gamma-secretase specificity. To discover selective inhibitors for drug development and for probing the mechanisms of gamma-secretase specificity, we screened chemical libraries and consequently developed a di-coumarin family of inhibitors that preferentially inhibit gamma-secretase-mediated production of Abeta42 over other cleavage activities. These coumarin dimer-based compounds interact with gamma-secretase by binding to an allosteric site. By developing a multiple photo-affinity probe approach, we demonstrate that this allosteric binding causes a conformational change within the active site of gamma-secretase at the S2 and S1 sub-sites that leads to selective inhibition of Abeta42. In conclusion, by using these di-coumarin compounds, we reveal a mechanism by which gamma-secretase specificity is regulated and provide insights into the molecular basis by which familial presenilin mutations may affect the active site and specificity of gamma-secretase. Furthermore, this class of selective inhibitors provides the basis for development of Alzheimer disease therapeutic agents. |
| Databáze: | OpenAIRE |
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