ArticleThe Journal of biological chemistry2013
γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
50 citing papers in PubMed, 103 citations in OpenAlex.
- γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.Alzheimer's research & therapy · 2025Article
- Target Identification of a Class of Pyrazolone Protein Aggregation Inhibitor Therapeutics for Amyotrophic Lateral Sclerosis.ACS central science · 2024Article
- Designing photoaffinity tool compounds for the investigation of the DENV NS2B-NS3 protease allosteric binding pocket.RSC medicinal chemistry · 2023Article
- Enzyme-substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP.The EMBO journal · 2022Article
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.Journal of cellular and molecular medicine · 2022Article
- Turning the tide on Alzheimer's disease: modulation of γ-secretase.Cell & bioscience · 2022Review
- Small-molecule drugs development for Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.The Journal of experimental medicine · 2020Article
- Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.Bioorganic & medicinal chemistry · 2020Article
- Article
- Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.RSC medicinal chemistry · 2020Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies.Clinical pharmacology and therapeutics · 2020Article
- 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
- Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response.PLoS computational biology · 2018Article
- Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.International journal of molecular sciences · 2018Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
γ-Secretase is an intramembrane aspartyl protease that cleaves the amyloid precursor protein to produce neurotoxic β-amyloid peptides (i.e. Aβ42) that have been implicated in the pathogenesis of Alzheimer disease. Small molecule γ-secretase modulators (GSMs) have emerged as potential disease-modifying treatments for Alzheimer disease because they reduce the formation of Aβ42 while not blocking the processing of γ-secretase substrates. We developed clickable GSM photoaffinity probes with the goal of identifying the target of various classes of GSMs and to better understand their mechanism of action. Here, we demonstrate that the photoaffinity probe E2012-BPyne specifically labels the N-terminal fragment of presenilin-1 (PS1-NTF) in cell membranes as well as in live cells and primary neuronal cultures. The labeling is competed in the presence of the parent imidazole GSM E2012, but not with acid GSM-1, allosteric GSI BMS-708163, or substrate docking site peptide inhibitor pep11, providing evidence that these compounds have distinct binding sites. Surprisingly, we found that the cross-linking of E2012-BPyne to PS1-NTF is significantly enhanced in the presence of the active site-directed GSI L-685,458 (L458). In contrast, L458 does not affect the labeling of the acid GSM photoprobe GSM-5. We also observed that E2012-BPyne specifically labels PS1-NTF (active γ-secretase) but not full-length PS1 (inactive γ-secretase) in ANP.24 cells. Taken together, our results support the hypothesis that multiple binding sites within the γ-secretase complex exist, each of which may contribute to different modes of modulatory action. Furthermore, the enhancement of PS1-NTF labeling by E2012-BPyne in the presence of L458 suggests a degree of cooperativity between the active site of γ-secretase and the modulatory binding site of certain GSMs.
Indexed as
Identifiers
What OpenQuestion holds
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 OpenQuestion graph.