PXD064685

PXD064685 is an original dataset announced via ProteomeXchange.

Title	Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO
Description	RNA-binding proteins (RBPs) play important roles in mRNA transcription, processing, and translation. Chemical tools are lacking for RBPs, which has hindered efforts to perturb and understand RBP function in cells. We recently reported a chloroacetamide compound (R)-SKBG-1 that covalently binds the RBP NONO and stabilizes its interactions with mRNAs, leading to transcriptional remodeling and the suppression of cancer cell growth. Here, we report the crystal structure of an (R)-SKBG-1:NONO complex, which confirms covalent modification of cysteine-145 at a pocket proximal to the RNA-binding interface of the protein. We show that this pocket can also be targeted by a lower reactivity chlorofluoroacetamide analog (R, R)-GL-373, which retains the pharmacological properties of (R)-SKBG-1, including blockade of estrogen receptor expression in breast cancer cells, while displaying much greater proteome-wide selectivity. Our findings thus show that NONO can be targeted by covalent ligands with high specificity to pharmacologically suppress pro-tumorigenic gene products in cancer cells.
HostingRepository	PRIDE
AnnounceDate	2026-02-23
AnnouncementXML	Submission_2026-02-22_17:40:19.489.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Garrett Lindsey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-05 07:33:51	ID requested
⏵ 1	2026-02-22 17:40:20	announced

10.1016/j.chembiol.2025.12.010;

Lindsey GL, Hockley TK, Gomez AV, Marshall AC, Brothers WR, Finney CT, Gross J, Fox AH, Yeo GW, Melillo B, Bond CS, Cravatt BF, Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO. Cell Chem Biol, 33(2):256-267.e11(2026) [pubmed]

submitter keyword: proteomics, chemical biology, RBPs, RNA-binding protein

Benjamin F. Cravatt
contact affiliation	Department of Chemistry, Scripps Research
contact email	cravatt@scripps.edu
lab head
Garrett Lindsey
contact affiliation	Scripps Research
contact email	glindsey@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/2026/02/PXD064685

PRIDE project URI

• PRIDE
  1. PXD064685
     1. Label: PRIDE project
     2. Name: Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO