Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO
Year: 2026
Type: article
Abstract: 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 previously described a chloroacetamide compound ( R )-SKBG-1 that covalently binds the RBP NONO and stabilizes its interactions with mRNAs, leading to transcriptional remodeling and 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.
Source: Cell chemical biology
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Awards: A high-throughput protein production and structure facility, G1864025174, G245757704, G267014303, Biomolecular Interaction Facility, A liquid protein platform for dynamic bio-inspired reaction compartments, An integrated molecular approach to human gene regulation, Engineering self-assembled intracellular biological condensates, DBHS protein RNA interactions in health and disease, eDyNAmiC - STANFORD, G4268089617, G5594779030, G7278273519, G8393059803, Integrated Crystallisation Facility, eDyNAmiC - SCRIPPS, Chemical Proteomic Platforms for Radically Expanding Cancer Druggability, Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.
OpenAlex ID: W7123473986