Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Christopher C. Shelton, Lei Zhu, Deming Chau, Li Yang, Rong Wang, Hakim Djaballah, Hui Zheng, Yue Ming Li

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageEnglish
Pages (from-to)20228-20233
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number48
DOIs
StatePublished - 1 Dec 2009

Keywords

  • Affinity labeling
  • Allosteric regulation
  • Alzheimer disease
  • Di-coumarin

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