ArticleStructure (London, England : 1993)2014
Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
Article in Structure (London, England : 1993), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Gamma secretase activity modulates BMP-7-induced dendritic growth in primary rat sympathetic neurons.Autonomic neuroscience : basic & clinical · 2023Article
- HPV is a cargo for the COPI sorting complex during virus entry.Science advances · 2023Article
- Role of cholesterol in substrate recognition by [Formula: see text]-secretase.Scientific reports · 2021Article
- Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer's Disease.Neurotoxicity research · 2020Review
- Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype.Frontiers in molecular neuroscience · 2020Review
- Structure and Function of the γ-Secretase Complex.Biochemistry · 2019Article
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
- A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.The Journal of cell biology · 2019Article
- Review
- Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction.Nature communications · 2018Article
- γ-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection.The Journal of cell biology · 2018Article
- Efficient production of a mature and functional gamma secretase protease.Scientific reports · 2018Article
- Membrane properties that shape the evolution of membrane enzymes.Current opinion in structural biology · 2018Review
- Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2018Review
- Combining in vitro and in silico Approaches to Find New Candidate Drugs Targeting the Pathological Proteins Related to the Alzheimer's Disease.Current neuropharmacology · 2018Review
- Allosteric Modulation of Intact γ-Secretase Structural Dynamics.Biophysical journal · 2017Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach.Chemical science · 2017Article
- The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force.Developmental cell · 2017Review
- High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100.Scientific reports · 2017Article
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Authors and funding
20 authors at 8 institutions in 4 countries.
Funding
Abstract
Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the "lateral gate" through which substrates access to the catalytic site.
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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 OpenQuestion graph.