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Updated: Jun 5, 2025

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms

Published on: January 25, 2018

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Structural basis of human γ-secretase inhibition by anticancer clinical compounds

Xuefei Guo1, Haotian Li1, Xiaoli Lu2,3,4

  • 1Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

Nature Structural & Molecular Biology
|December 9, 2024
PubMed

Insights

Researchers mapped the structures of human γ-secretase bound to five gamma-secretase inhibitors (GSIs). These structures reveal how GSIs interact with the enzyme, offering insights for developing more potent anticancer drugs.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Aberrant Notch signaling, involving the Notch intracellular domain (NICD), is implicated in various cancers.
  • NICD release is mediated by γ-secretase activity, making γ-secretase inhibitors (GSIs) a promising anticancer strategy.

Purpose of the Study:

  • To determine the high-resolution cryo-electron microscopy structures of human γ-secretase in complex with five clinically evaluated GSIs.
  • To elucidate the binding interactions and structural basis for GSI activity within the γ-secretase complex.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to obtain structures of human γ-secretase bound to RO4929097, crenigacestat, BMS906024, nirogacestat, and MK-0752.
  • High-resolution structural analysis (2.4–3.0 Å) was performed on the GSI-γ-secretase complexes.

Main Results:

  • Structures revealed that all five GSIs bind to the substrate-binding site of presenilin 1 within the γ-secretase complex.
  • Distinct binding patterns were observed for each GSI, indicating specific recognition differences.
  • The bound GSI influences the conformation of the binding pocket, affecting its size and shape.

Conclusions:

  • The determined structures provide detailed molecular insights into GSI inhibition of γ-secretase.
  • Understanding these structural features and binding modes can guide the rational design of novel GSIs with enhanced anticancer potency.

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