2. Academic Validation
  3. Structural basis of γ-secretase inhibition and modulation by small molecule drugs

Structural basis of γ-secretase inhibition and modulation by small molecule drugs

  • Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049.
Guanghui Yang 1,  Rui Zhou 2,  Xuefei Guo 2,  Chuangye Yan 2,  Jianlin Lei 3,  Yigong Shi 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 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; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Xihu District, Hangzhou 310024, Zhejiang Province, China; Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Xihu District, Hangzhou 310024, Zhejiang Province, China. Electronic address: syg@westlake.edu.cn.
PMID: 33373587 DOI: 10.1016/j.cell.2020.11.049
Abstract

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.

Keywords

cryo-EM; drug; inhibitor; modulator; structure; γ-secretase.

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