Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase
View/ Open
Issue Date
2020-01-30Author
Bhattarai, Sanjay
Devkota, Sujan
Meneely, Kathleen M.
Xing, Minli
Douglas, Justin T.
Wolfe, Michael S.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
Copyright © 2020 American Chemical Society
Metadata
Show full item recordAbstract
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 complex that contain an N-terminal helical peptide region that engages a substrate docking exosite and a C-terminal transition-state analog moiety targeted to the active site. Both regions are required for stoichiometric inhibition of γ-secretase. Moreover, enzyme inhibition kinetics and photoaffinity probe displacement experiments demonstrate that both the docking exosite and the active site are engaged by the bipartite inhibitors. The solution conformations of these potent transmembranemimetic inhibitors are similar to those of bound natural substrates, suggesting these probes are preorganized for high-affinity binding and should allow visualization of the active γ-secretase complex, poised for intramembrane proteolysis, by cryo-electron microscopy.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in
Journal of the American Chemical Society (JACS), copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.9b13405.
Collections
Citation
Bhattarai, S., Devkota, S., Meneely, K. M., Xing, M., Douglas, J. T., & Wolfe, M. S. (2020). Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase. Journal of the American Chemical Society, 142(7), 3351–3355. https://doi.org/10.1021/jacs.9b13405
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.