PXD046356

PXD046356 is an original dataset announced via ProteomeXchange.

Title	Proteomic ligandability maps of spirocycle acrylamides identify covalent ERCC3 degraders
Description	Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regio-chemically defined spirocycle acrylamides and their analysis in human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared to structurally related azetidine acrylamides, the spirocycle acrylamides preferentially liganded specific cysteines on diverse protein classes. One compound ZL-12A stereoselectively promoted the degradation of the TFIIH helicase ERCC3. Interestingly, ZL-12A reacts with the same cysteine (C342) in ERCC3 as the natural product triptolide, which did not lead to ERCC3 degradation but instead caused collateral loss of RNA polymerases. ZL-12A and triptolide cross-antagonized one another’s protein degradation profiles. Finally, we show that the anti-hypertension drug spironolactone — previously found to promote ERCC3 degradation through an enigmatic mechanism — also reacts with ERCC3_C342. Our findings thus describe monofunctional degraders of ERCC3 and highlight how covalent ligands targeting the same cysteine can produce strikingly different functional outcomes.
HostingRepository	PRIDE
AnnounceDate	2025-11-07
AnnouncementXML	Submission_2025-11-06_16:49:44.505.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhonglin Liu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-24 06:37:07	ID requested
⏵ 1	2025-11-06 16:49:45	announced

10.1021/JACS.3C13448;

submitter keyword: Proteomics, chemical biology

Benjamin Cravatt
contact affiliation	Department of Chemistry, Scripps Research
contact email	cravatt@scripps.edu
lab head
Zhonglin Liu
contact affiliation	Scripps Research
contact email	zhliu@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/11/PXD046356

PRIDE project URI

• PRIDE
  1. PXD046356
     1. Label: PRIDE project
     2. Name: Proteomic ligandability maps of spirocycle acrylamides identify covalent ERCC3 degraders