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PXD048457-1

PXD048457 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleChemoproteomic screen to identify rabeprazole off-targets in intact HEK293 MSR cells
DescriptionProton pump inhibitors (PPIs) have become top-selling drugs worldwide. They are prodrugs activated by protonation in highly acidic environments. They inhibit stomach acid secretion by covalently modifying the gastric H+/K+-ATPase. However, little is known about alternative activation mechanisms and target proteins in non-acidic environments. Employing a chemoproteomic approach in living cells, we find rabeprazole to form covalent conjugates with numerous zinc-binding proteins. We show that one of the main target proteins, density-regulated protein (DENR), is conjugated to rabeprazole through a cysteine residue forming part of the zinc-binding site. We propose that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation of PPIs in non-acidic environments. Our findings may aid the understanding of secondary drug effects and/or the repurposing of PPIs.
HostingRepositoryPRIDE
AnnounceDate2025-01-30
AnnouncementXMLSubmission_2025-01-29_23:28:15.604.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterFrank Stein
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListN-ethylmaleimide derivatized cysteine; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-01-11 05:31:46ID requested
12025-01-29 23:28:15announced
Publication List
10.1038/S41557-025-01745-8;
Keyword List
submitter keyword: Drug Target Screen, Chemoproteomics,Proton Pump Inhibitor, Rabeprazole
Contact List
Tobias P Dick
contact affiliationDivision of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
contact emailt.dick@dkfz.de
lab head
Frank Stein
contact affiliationEMBL
contact emailfrank.stein@embl.de
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
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