早老素
生物
变构调节
细胞外
淀粉样前体蛋白分泌酶
细胞生物学
结合位点
淀粉样前体蛋白
生物化学
生物物理学
神经科学
阿尔茨海默病
酶
疾病
医学
病理
作者
Guanghui Yang,Rui Zhou,Xuefei Guo,Chuangye Yan,Jianlin Lei,Yigong Shi
出处
期刊:Cell
[Elsevier]
日期:2021-01-01
卷期号:184 (2): 521-533.e14
被引量:94
标识
DOI:10.1016/j.cell.2020.11.049
摘要
Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer’s disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6–3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.
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