IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33817-5.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33817-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33817-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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. 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.
    3. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Melanie A. Orlando & Hunter J. T. Pouillon & Saikat Mandal & Lee Kroos & Benjamin J. Orlando, 2024. "Substrate engagement by the intramembrane metalloprotease SpoIVFB," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. 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.
    3. Xia Wang & Jiayu Wang & Yashuang Chen & Xiaojing Qian & Shiqi Luo & Xue Wang & Chao Ma & Wei Ge, 2024. "The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33817-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.