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PXD061182

PXD061182 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDiscovery and optimisation of a covalent ligand for TRIM25 and its application to targeted protein ubiquitination
DescriptionThe tripartite motif (TRIM) family of RING-type E3 ligases catalyses the formation of many different types of ubiquitin chains, and as such, plays important roles in diverse cellular functions, ranging from immune regulation to cancer signalling pathways. Few ligands have been discovered for TRIM E3 ligases, and these E3s are under-represented in the rapidly expanding field of induced proximity. Here we present the identification of a novel covalent ligand for the PRYSPRY substrate binding domain of TRIM25. We employ covalent fragment screening coupled with high-throughput chemistry direct-to-biology optimisation to efficiently elaborate covalent fragment hits. We demonstrate that our optimised ligand enhances the in vitro auto-ubiquitination activity of TRIM25 and engages TRIM25 in live cells. We also present the X-ray crystal structure of TRIM25 PRYSPRY in complex with this covalent ligand. Finally, we incorporate our optimised ligand into heterobifunctional proximity-inducing compounds and demonstrate the in vitro targeted ubiquitination of a neosubstrate by TRIM25
HostingRepositoryPRIDE
AnnounceDate2025-05-19
AnnouncementXMLSubmission_2025-05-19_10:49:07.045.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterKatherine McPhie
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Eclipse
Dataset History
RevisionDatetimeStatusChangeLog Entry
02025-02-25 08:06:42ID requested
12025-05-19 10:49:07announced
Publication List
10.1039/D5SC01540E;
Keyword List
submitter keyword: covalent ligand,E3 Ligase, ubiquitin, IA-DTB
Contact List
Katrin Rittinger
contact affiliationMolecular Structure of Cell Signalling Laboratory, The Francis Crick Institute
contact emailkatrin.rittinger@crick.ac.uk
lab head
Katherine McPhie
contact affiliationThe Francis Crick Institute
contact emailkatherine.mcphie@crick.ac.uk
dataset submitter
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Dataset FTP location
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PRIDE project URI
Repository Record List
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