Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560

Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer’s disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains e...

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Published in:Nature communications 2022-10, Vol.13 (1), p.6299-6299, Article 6299
Main Authors: Guo, Xuefei, Wang, Yumeng, Zhou, Jiayao, Jin, Chen, Wang, Jiaoni, Jia, Bojun, Jing, Dan, Yan, Chuangye, Lei, Jianlin, Zhou, Rui, Shi, Yigong
Format: Article
Language:English
Subjects:
101/28
631/45/607/468
631/45/612/1237
631/535/1258/1259
Alzheimer's disease
Amyloid Precursor Protein Secretases - metabolism
Binding sites
Cryoelectron Microscopy
Electron microscopy
Humanities and Social Sciences
Isoforms
Kinases
multidisciplinary
Neurodegenerative diseases
Presenilin 1
Presenilin 2
Presenilin-1 - genetics
Presenilin-1 - metabolism
Protein Isoforms
Science
Science (multidisciplinary)
Secretase
Selectivity
Sensitivity
Substrates
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Summary:Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer’s disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting γ-secretase. Presenilin isoforms (PS1 and PS2) containing γ-secretase show contrasting sensitivity to MRK-560. Here, the authors determined cryo-EM structures of PS1/PS2-complexes treated with MRK-560 and identified key residues responsible for the isoform-dependent selectivity.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-33817-5