ArticleProceedings of the National Academy of Sciences of the United States of America2014
Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 72 citations in OpenAlex.
- 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
- APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.The EMBO journal · 2023Article
- Enzyme-substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP.The EMBO journal · 2022Article
- Targeting Common Signaling Pathways for the Treatment of Stroke and Alzheimer's: a Comprehensive Review.Neurotoxicity research · 2021Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 2020Article
- Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.EMBO reports · 2020Article
- Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.Frontiers in molecular neuroscience · 2020Review
- Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators.The EMBO journal · 2019Article
- Influence of membrane lipid composition on the structure and activity of γ-secretase.Physical chemistry chemical physics : PCCP · 2018Article
- Review
- Both positional and chemical variables controlThe Journal of biological chemistry · 2018Article
- Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2018Review
- Allosteric Modulation of Intact γ-Secretase Structural Dynamics.Biophysical journal · 2017Article
- Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- DynOmics: dynamics of structural proteome and beyond.Nucleic acids research · 2017Article
- Cell-free methods to produce structurally intact mammalian membrane proteins.Scientific reports · 2016Article
- Therapies for Prevention and Treatment of Alzheimer's Disease.BioMed research international · 2016Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-β (Aβ) peptides. Recently, a series of compounds called γ-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Aβ species (i.e., Aβ42), with a concomitant elevation of the production of shorter Aβ species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of γ-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of γ-secretase to modulate Aβ production.
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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 OpenQuestion graph.