2020
DOI: 10.1021/jacs.9b13405
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Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase

Abstract: γ-Secretase is a membrane-embedded aspartyl protease complex central in biology and medicine. How this enzyme recognizes transmembrane substrates and catalyzes hydrolysis in the lipid bilayer is unclear. Inhibitors that mimic the entire substrate transmembrane domain and engage the active site should provide important tools for structural biology, yielding insight into substrate gating and trapping the protease in the active state. Here we report transmembrane peptidomimetic inhibitors of the γ-secretase compl… Show more

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Cited by 12 publications
(46 citation statements)
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“…More recently, HPI and TSA inhibitors have been combined to create substrate-based structural probes for the γ-secretase complex [ 62 ]. The structure of the γ-secretase complex was elucidated by cryo-electron microscopy (cryo-EM) in 2015 [ 63 ].…”
Section: Structural Probesmentioning
confidence: 99%
See 3 more Smart Citations
“…More recently, HPI and TSA inhibitors have been combined to create substrate-based structural probes for the γ-secretase complex [ 62 ]. The structure of the γ-secretase complex was elucidated by cryo-electron microscopy (cryo-EM) in 2015 [ 63 ].…”
Section: Structural Probesmentioning
confidence: 99%
“…Thus, the enzyme was catalytically inactive, and the Cys mutations with crosslinking raised the possibility of artifacts. To trap the active enzyme without crosslinking, full TMD substrate-based mimetics were recently developed as tight-binding inhibitors of γ-secretase [ 62 ]. In the design of these structural probes, linking 10-residue helical peptide inhibitors (HPIs) to transition-state analog inhibitors (TSA) was envisioned to provide potent inhibitors that would simultaneously bind to both the docking site and active site.…”
Section: Structural Probesmentioning
confidence: 99%
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“…For cross-competition studies between two inhibitors, enzyme reactions were run as activity assays, where varying concentration of two inhibitors were titrated against each-other, keeping the concentrations of C100 (0.50 μM) constant. 31,41 Reciprocal plots were generated, and data were fit using GraphPad Prism 9.0 into the following equation:…”
Section: Cross-competition Kinetic Experimentsmentioning
confidence: 99%