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

Author

Listed:
  • 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
    Westlake University, Xihu District
    Westlake Institute for Advanced Study, Xihu District)

  • Chuangye Yan

    (Tsinghua University)

  • Jianlin Lei

    (Tsinghua University)

  • Rui Zhou

    (Tsinghua University)

  • Yigong Shi

    (Tsinghua University
    Westlake Laboratory of Life Science and Biomedicine, Xihu District
    Westlake University, Xihu District
    Westlake Institute for Advanced Study, Xihu District)

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.

Suggested Citation

  • Xuefei Guo & Yumeng Wang & Jiayao Zhou & Chen Jin & Jiaoni Wang & Bojun Jia & Dan Jing & Chuangye Yan & Jianlin Lei & Rui Zhou & Yigong Shi, 2022. "Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33817-5
    DOI: 10.1038/s41467-022-33817-5
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    References listed on IDEAS

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    1. Bart De Strooper & Paul Saftig & Katleen Craessaerts & Hugo Vanderstichele & Gundula Guhde & Wim Annaert & Kurt Von Figura & Fred Van Leuven, 1998. "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein," Nature, Nature, vol. 391(6665), pages 387-390, January.
    2. Guanghui Yang & Rui Zhou & Qiang Zhou & Xuefei Guo & Chuangye Yan & Meng Ke & Jianlin Lei & Yigong Shi, 2019. "Structural basis of Notch recognition by human γ-secretase," Nature, Nature, vol. 565(7738), pages 192-197, January.
    3. Bart De Strooper & Wim Annaert & Philippe Cupers & Paul Saftig & Katleen Craessaerts & Jeffrey S. Mumm & Eric H. Schroeter & Vincent Schrijvers & Michael S. Wolfe & William J. Ray & Alison Goate & Rap, 1999. "A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain," Nature, Nature, vol. 398(6727), pages 518-522, April.
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    Cited by:

    1. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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