PXD067054

PXD067054 is an original dataset announced via ProteomeXchange.

Title	A Gold-PROTAC degrades the oncogenic tyrosine kinase MERKT: Insights into the degradome from a steady-state system
Description	Targeted protein degradation is a valuable strategy to eliminate disease-relevant proteins. Among other classes, proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce the proximity of a recruiter E3 ligase and the target protein of interest for ubiquitination and subsequent degradation by the proteasome. While most PROTACs are non-covalent interactors, covalent PROTACs may benefit from increased selectivity and altered pharmacodynamics, yet remain largely understudied. In this context, a gold-based metallo-PROTAC (AuPROTAC) was synthesized, consisting of a cyclometalated Au(III) complex based on a bidentate C^N-ligand, which induces covalent cysteine/selenocysteine-arylation in a gold-templated two-step mechanism. This was then linked to a cereblon binding moiety. The degradome of the covalent AuPROTAC was characterized by establishing a cycloheximide chase assay, which was performed in a non-proliferative steady-state cell culture system that maintained a static protein turnover and efficiently decouples protein degradation from down-regulation. The method was verified with the known SMARCA2 and PBRM1-degrader ACBI2. The AuPROTAC was found to degrade MERTK and TXNL1, while their degradation was successfully rescued by proteasome inhibition. Since MERTK does not contain a cysteine in the active binding pocket, AuPROTAC is believed to covalently modify this protein at an allosteric site, leading to its degradation by the proteasome. The PROTACs were found to affect protein half-lives in this cycloheximide chase assay. Therefore, proteome-wide degradation selectivity was further characterized by ranking degraded targets based on the acceleration of protein half-lives. Overall, the established approach can be used to efficiently explore degradomes of CRBN and VHL recruiter-based PROTACs.
HostingRepository	PRIDE
AnnounceDate	2026-07-27
AnnouncementXML	Submission_2026-07-27_07:38:56.005.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christopher Gerner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-07 05:35:17	ID requested
⏵ 1	2026-07-27 07:38:56	announced

10.1021/ACSCHEMBIO.5C00860;

submitter keyword: Cancer

Degradome

Metallo-PROTAC

PROTAC

Protein half-life

Targeted protein degradation

Christopher Gerner
contact affiliation	University of Vienna, Faculty of Chemistry, Department of Analytical Chemistry
contact email	christopher.gerner@univie.ac.at
lab head
Christopher Gerner
contact affiliation	University of Vienna
contact email	christopher.gerner@univie.ac.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067054
     1. Label: PRIDE project
     2. Name: A Gold-PROTAC degrades the oncogenic tyrosine kinase MERKT: Insights into the degradome from a steady-state system