Enzyme–substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP

Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucía Chávez-Gutiérrez

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Alzheimer's disease (AD) pathogenesis has been linked to the accumulation of longer, aggregation-prone amyloid β (Aβ) peptides in the brain. Γ-secretases generate Aβ peptides from the amyloid precursor protein (APP). Γ-secretase modulators (GSMs) promote the generation of shorter, less-amyloidogenic Aβs and have therapeutic potential. However, poorly defined drug–target interactions and mechanisms of action have hampered their therapeutic development. Here, we investigate the interactions between the imidazole-based GSM and its target γ-secretase—APP using experimental and in silico approaches. We map the GSM binding site to the enzyme–substrate interface, define a drug-binding mode that is consistent with functional and structural data, and provide molecular insights into the underlying mechanisms of action. In this respect, our analyses show that occupancy of a γ-secretase (sub)pocket, mediating binding of the modulator's imidazole moiety, is sufficient to trigger allosteric rearrangements in γ-secretase as well as stabilize enzyme–substrate interactions. Together, these findings may facilitate the rational design of new modulators of γ-secretase with improved pharmacological properties.

Original languageEnglish
Article numbere111084
JournalEMBO Journal
Volume41
Issue number21
DOIs
StatePublished - 2 Nov 2022
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid precursor protein
  • amyloid β
  • preselinin
  • γ-secretase
  • γ-secretase modulators

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