PXD037297

PXD037297 is an original dataset announced via ProteomeXchange.

Title	Chemoproteomic profiling to identify activity changes and functional inhibitors of DNA-binding proteins
Description	DNA-binding proteins are promising therapeutic targets but notoriously difficult to drug. Here, we evaluate a chemoproteomic DNA interaction platform as a complementary strategy for parallelized compound profiling. To enable this approach, we determined the proteomic binding landscape of 92 immobilized DNA sequences. Perturbation-induced activity changes of captured transcription factors in disease-relevant settings demonstrated functional relevance of the enriched sub-proteome. Chemoproteomic profiling of >300 cysteine-directed compounds against a coverage optimized bead mixture, which specifically captures >150 DNA binders, revealed competition of several DNA-binding proteins, including the transcription factors ELF1 and ELF2. We also discovered the first compound which displaces the DNA-repair complex MSH2-MSH3 from DNA. Compound binding to cysteine 252 on MSH3 was confirmed using chemoproteomic reactive cysteine profiling. Overall, these results suggested that chemoproteomic DNA bead pull-downs enable the specific read-out of transcription factor activity and can identify functional “hot-spots” on DNA binders towards expanding the druggable proteome.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:45:33.050.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	benjamin ruprecht
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-11 06:10:03	ID requested
1	2023-02-03 15:35:38	announced
⏵ 2	2023-11-14 07:45:38	announced	2023-11-14: Updated project metadata.

Ruprecht B, Wei L, Zheng L, Bodea S, Mo X, Maschberger M, Stoehr G, Hahne H, Cornella-Taracido I, Chi A, Chemoproteomic profiling to identify activity changes and functional inhibitors of DNA-binding proteins. Cell Chem Biol, 29(11):1639-1648.e4(2022) [pubmed]

submitter keyword: reactive side chain profiling, mass spectrometry, drug screening, pull-down, covalency, DNA binding,Chemical proteomics

An Chi
contact affiliation	Merck Research Laboratories, Boston, MA, USA
contact email	An_Chi@merck.com
lab head
benjamin ruprecht
contact affiliation	Merck
contact email	benruprecht85@gmail.com
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/2023/02/PXD037297

PRIDE project URI

• PRIDE
  1. PXD037297
     1. Label: PRIDE project
     2. Name: Chemoproteomic profiling to identify activity changes and functional inhibitors of DNA-binding proteins