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

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 m

SUBMITTER: Petit D 

PROVIDER: S-EPMC9627667 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature