PXD064043-1

PXD064043 is an original dataset announced via ProteomeXchange.

Title	Integration dynamic combinatorial library with activity-based protein profiling for library-versus-library covalent ligand discovery
Description	This platform generates compound libraries in situ, allowing proteins to template the formation of optimal ligands, while ABPP provides a high-throughput, mass spectrometry-based readout for ligand screening. We applied this platform to discover covalent inhibitors for serine hydrolases, including PPME1, ABHD11, and PNPLA6, achieving nanomolar potency. Using the PNPLA6 inhibitor as a tool compound, lipidomics studies revealed its role in lipid metabolism and cancer cell proliferation, providing new insights into the enzyme's biological function. We also extended this approach to cysteine-targeting covalent ligand discovery by introducing novel scaffolds—chloroacetohydrazone and acrylohydrazone—that are compatible with DCL and selectively label cysteine residues. By integrating a TMT-based workflow, we identified over 2,600 ligandable cysteine sites across the proteome, with EC50 values determined for each site. This method enabled the discovery of first reported inhibitors for enzymes such as NIT2, PRDX5, and TXNDC17. Additionally, we used a cytotoxic ligand identified through cell viability assays as a tool compound to study the regulatory proteins re-translated following VCP inhibition, which induces paraptosis by causing the accumulation of degraded proteins.
HostingRepository	iProX
AnnounceDate	2025-05-19
AnnouncementXML	Submission_2025-05-18_23:50:07.139.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuchen Huang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	TMT6plex reporter fragment
Instrument	Q Exactive Plus; Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-18 23:43:55	ID requested
⏵ 1	2025-05-18 23:50:07	announced

Dataset with its publication pending

submitter keyword: library-versus-library, dynamic combinatorial library, ligang discovery

Gang Li
contact affiliation	Shenzhen Bay Laboratory
contact email	ligang@szbl.ac.cn
lab head
Yuchen Huang
contact affiliation	Shenzhen Bay Laboratory
contact email	hychen824@163.com
dataset submitter

iProX dataset URI