Piperidine Acetic Acid Based γ-Secretase Modulators Directly Bind to Presenilin-1

被引:53
作者
Crump, Christina J. [2 ,3 ]
Fish, Benjamin A. [1 ]
Castro, Suita V. [2 ]
Chau, De-Ming [2 ,3 ]
Gertsik, Natalya [2 ,4 ]
Ahn, Kwangwook [2 ]
Stiff, Cory [1 ]
Pozdnyakov, Nikolay [1 ]
Bales, Kelly R. [1 ]
Johnson, Douglas S. [1 ]
Li, Yue-Ming [2 ,3 ]
机构
[1] Pfizer Worldwide Res & Dev, Groton, CT 06340 USA
[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA
[3] Cornell Univ, Dept Pharmacol, Weill Grad Sch Med Sci, New York, NY 10021 USA
[4] Cornell Univ, Dept Biochem & Mol Biol, Weill Grad Sch Med Sci, New York, NY 10021 USA
来源
ACS CHEMICAL NEUROSCIENCE | 2011年 / 2卷 / 12期
关键词
Alzheimer's disease; presenilin; gamma-secretase modulator; GSM-1; click chemistry; photoaffinity labeling; CLICK CHEMISTRY; A-BETA; ALZHEIMERS-DISEASE; INHIBITORS; PROTEIN; TARGET; IDENTIFICATION; SPECIFICITY; ACTIVATION; PROTEOMICS;
D O I
10.1021/cn200098p
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A beta 42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. gamma-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of A beta 42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the gamma-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the gamma-secretase complex leading to the observed modulation of gamma-secretase activity.
引用
收藏
页码:705 / 710
页数:6
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