Beijing Advanced Innovation Center for Structural Biology and Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China; State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Beijing Advanced Innovation Center for Structural Biology and Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049. Epub 2020 Dec 28.
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.
γ-分泌酶抑制剂（GSIs）和调节剂（GSMs）的开发为阿尔茨海默病（AD）和癌症提供了一种有吸引力的治疗机会。然而，这些 GSIs 和 GSMs 如何靶向 γ-分泌酶在很大程度上仍不清楚。在这里，我们报告了人 γ-分泌酶分别与两种 GSI 临床候选药物、Semagacestat 和 Avagacestat、过渡态模拟 GSI L685,458 和经典 GSM E2012 结合的冷冻电镜（cryo-EM）结构，整体分辨率为 2.6-3.1 Å。值得注意的是，每种 GSI 都占据了早老素 1（PS1）上相同的一般位置，该位置容纳了淀粉样前体蛋白或 Notch 的β链，干扰了底物募集。L685,458 直接与 PS1 的两个催化天冬氨酸残基配位。E2012 结合到 γ-分泌酶外表面的变构位点上，可能解释了其调节活性。结构分析揭示了抑制剂和调节剂识别的一组共同主题和变化，这将指导下一代底物选择性抑制剂的开发。
