ArticleNature communications2022
Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.International journal of molecular sciences · 2026Article
- Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.Frontiers in cell and developmental biology · 2026Review
- Virtual screening of drugs against multiple targets of Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Article
- Social memory maintenance relies on social interaction-induced proteolytic products of neuroligin 1.Signal transduction and targeted therapy · 2025Article
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- Structural basis of human γ-secretase inhibition by anticancer clinical compounds.Nature structural & molecular biology · 2025Article
- Identification of AS1842856 as a novel small-molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis.Aging cell · 2025Article
- Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.Nature communications · 2024Article
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.Communications biology · 2023Article
- Selective inhibitors of the PSEN1-gamma-secretase complex.The Journal of biological chemistry · 2023Article
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- γ-secretase targeting in Alzheimer's disease.Journal of Alzheimer's disease reportsReview
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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