2020 年 12 月 28 日，中科院院士、西湖大學校長施一公教授團隊在 Cell 上在線發(fā)表了題為 Structural basis of γ-secretase inhibition and modulation by small molecule drugs《 小分子藥物抑制和調節(jié)γ-分泌酶的結構基礎》的研究成果。據(jù)悉， 施一公教授為該論文通訊作者，中國農業(yè)大學楊光輝與清華大學生命學院助理研究員周瑞、博士生郭雪飛為論文的共同第一作者。
研究首次報道了 γ- 分泌酶（γ-secretase）結合兩種小分子抑制劑（Gamma-Secretase Inhibitor, GSI）和一種調節(jié)劑（Gamma-Secretase Modulator, GSM）的 4 個原子分辨率冷凍電鏡結構，闡明了 γ- 分泌酶識別不同種類抑制劑及調節(jié)劑的分子機理。

據(jù)該論文第一作者中國農業(yè)大學教授楊光輝接受《中國科學報》采訪時介紹，這項工作將為研究阿茲海默癥以及癌癥相關具有底物選擇性的 γ- 分泌酶抑制劑提供重要的結構信息。

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 ?. 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.