Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
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ABSTRACT:
SUBMITTER: Guo X
PROVIDER: S-EPMC9587990 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
Guo Xuefei X Wang Yumeng Y Zhou Jiayao J Jin Chen C Wang Jiaoni J Jia Bojun B Jing Dan D Yan Chuangye C Lei Jianlin J Zhou Rui R Shi Yigong Y
Nature communications 20221022 1
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 ...[more]
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