Modulation of γ-secretase specificity using small molecule allosteric inhibitors Journal Article
| Authors: | Shelton, C. C.; Zhu, L.; Chau, D.; Yang, L.; Wang, R.; Djaballah, H.; Zheng, H.; Li, Y. M. |
| Article Title: | Modulation of γ-secretase specificity using small molecule allosteric inhibitors |
| Abstract: | γ-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 γ-secretase specificity. To discover selective inhibitors for drug development and for probing the mechanisms of γ-secretase specificity, we screened chemical libraries and consequently developed a di-coumarin family of inhibitors that preferentially inhibit γ-secretase-mediated production of Aβ42 over other cleavage activities. These coumarin dimerbased compounds interact withγ-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 γ-secretase at the S2 and S1 sub-sites that leads to selective inhibition of Aβ42. In conclusion, by using these di-coumarin compounds, we reveal a mechanism by which γ-secretase specificity is regulated and provide insights into the molecular basis by which familial presenilin mutations may affect the active site and specificity of γ-secretase. Furthermore, this class of selective inhibitors provides the basis for development of Alzheimer disease therapeutic agents. |
| Keywords: | mutation; protein conformation; protein binding; drug discovery; molecular library; small molecule libraries; enzyme regulation; kinetics; screening; substrate specificity; binding site; conformational transition; alzheimer disease; amyloid precursor protein secretases; gamma secretase; photoaffinity labeling; photoaffinity labels; affinity labeling; allosteric regulation; di-coumarin; coumarin; allosterism; modulation; amyloid beta-protein; coumarins; presenilins |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 106 |
| Issue: | 48 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2009-12-01 |
| Start Page: | 20228 |
| End Page: | 20233 |
| Language: | English |
| DOI: | 10.1073/pnas.0910757106 |
| PUBMED: | 19906985 |
| PROVIDER: | scopus |
| PMCID: | PMC2787169 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus" |
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