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dc.contributor.authorBhattarai, Sanjay
dc.contributor.authorDevkota, Sujan
dc.contributor.authorMeneely, Kathleen M.
dc.contributor.authorXing, Minli
dc.contributor.authorDouglas, Justin T.
dc.contributor.authorWolfe, Michael S.
dc.date.accessioned2020-10-21T14:41:29Z
dc.date.available2020-10-21T14:41:29Z
dc.date.issued2020-01-30
dc.identifier.citationBhattarai, 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.9b13405en_US
dc.identifier.urihttp://hdl.handle.net/1808/30796
dc.descriptionThis 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.en_US
dc.description.abstractγ-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.en_US
dc.description.sponsorshipNIH R01 grant GM 122894en_US
dc.description.sponsorshipNIH grant P30GM110761en_US
dc.description.sponsorshipNIH grant P41GM111135en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsCopyright © 2020 American Chemical Societyen_US
dc.subjectInhibitorsen_US
dc.subjectInhibitionen_US
dc.subjectPeptides and proteinsen_US
dc.subjectLabelingen_US
dc.subjectProbesen_US
dc.titleDesign of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretaseen_US
dc.typeArticleen_US
kusw.kuauthorBhattarai, Sanjay
kusw.kuauthorDevkota, Sujan
kusw.kuauthorMeneely, Kathleen M.
kusw.kuauthorXing, Minli
kusw.kuauthorDouglas, Justin T.
kusw.kuauthorWolfe, Michael S.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.kudepartmentBiomolecular NMR Laboratoryen_US
dc.identifier.doi10.1021/jacs.9b13405en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-5721-9092en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7359870en_US
dc.rights.accessrightsembargoedAccessen_US


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