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

Xuefei Guo, Yumeng Wang, Jiayao Zhou, Chen Jin, Jiaoni Wang, Bojun Jia, Dan Jing, Chuangye Yan, Jianlin Lei, Rui Zhou () and Yigong Shi ()
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Xuefei Guo: Tsinghua University
Yumeng Wang: Tsinghua University
Jiayao Zhou: Tsinghua University
Chen Jin: Tsinghua University
Jiaoni Wang: Tsinghua University
Bojun Jia: Tsinghua University
Dan Jing: Westlake Laboratory of Life Science and Biomedicine, Xihu District
Chuangye Yan: Tsinghua University
Jianlin Lei: Tsinghua University
Rui Zhou: Tsinghua University
Yigong Shi: Tsinghua University

Nature Communications, 2022, vol. 13, issue 1, 1-7

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33817-5

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