阿尔兹海默症新突破：施一公团队再解重要蛋白结构

2020 年 12 月 28 日，中科院院士、西湖大学校长施一公教授团队在 Cell 上在线发表了题为 Structural basis of γ-secretase inhibition and modulation by small molecule drugs《 小分子药物抑制和调节γ-分泌酶的结构基础》的研究成果。据悉， 施一公教授为该论文通讯作者，中国农业大学杨光辉与清华大学生命学院助理研究员周瑞、博士生郭雪飞为论文的共同第一作者。
研究首次报道了 γ- 分泌酶（γ-secretase）结合两种小分子抑制剂（Gamma-Secretase Inhibitor, GSI）和一种调节剂（Gamma-Secretase Modulator, GSM）的 4 个原子分辨率冷冻电镜结构，阐明了 γ- 分泌酶识别不同种类抑制剂及调节剂的分子机理。

据该论文第一作者中国农业大学教授杨光辉接受《中国科学报》采访时介绍，这项工作将为研究阿兹海默症以及癌症相关具有底物选择性的 γ- 分泌酶抑制剂提供重要的结构信息。

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.