ArticleRSC advances2020
Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.
Article in RSC advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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Who cites it
10 citing papers in PubMed, 34 citations in OpenAlex.
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.Chemical reviews · 2026Review
- Structural Dynamics of Neutral Amino Acid Transporter SLC6A19 in Simple and Complex Lipid Bilayers.Journal of cellular biochemistry · 2025Article
- Article
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- Formation of extramembraneProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase.Journal of the American Chemical Society · 2022Article
- Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions inFrontiers in pharmacology · 2022Article
- MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics.Computational and structural biotechnology journal · 2021Article
- Novel dynamic residue network analysis approaches to study allosteric modulation: SARS-CoV-2 MComputational and structural biotechnology journal · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase cleaves the C99 fragment of the amyloid precursor protein, leading to formation of aggregated β-amyloid peptide central to Alzheimer's disease, and Notch, essential for cell regulation. Recent cryogenic electron microscopy (cryo-EM) structures indicate major changes upon substrate binding, a β-sheet recognition motif, and a possible helix unwinding to expose peptide bonds towards nucleophilic attack. Here we report side-by-side comparison of the 303 K dynamics of the two proteins in realistic membranes using molecular dynamics simulations. Our ensembles agree with the cryo-EM data (full-protein Cα-RMSD = 1.62-2.19 Å) but reveal distinct presenilin helix conformation states and thermal β-strand to coil transitions of C83 and Notch100. We identify distinct 303 K hydrogen bond dynamics and water accessibility of the catalytic sites. The RKRR motif (1758-1761) contributes significantly to Notch binding and serves as a "membrane anchor" that prevents Notch displacement. Water that transiently hydrogen bonds to G1753 and V1754 probably represents the catalytic nucleophile. At 303 K, Notch and C83 binding induce different conformation states, with Notch mostly present in a closed state with shorter Asp-Asp distance. This may explain the different outcome of Notch and C99 cleavage, as the latter is more imprecise with many products. Our identified conformation states may aid efforts to develop conformation-selective drugs that target C99 and Notch cleavage differently,
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.