期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：48
页码：20228-20233
DOI：10.1073/pnas.0910757106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{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 A{beta}42 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 A{beta}42. 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.
