9NZI

NONO homodimer bound to (R)-SKBG-1

This is a non-PDB format compatible entry.

Summary for 9NZI

• Entry DOI: 10.2210/pdb9nzi/pdb
• Descriptor: Non-POU domain-containing octamer-binding protein, (2R)-4-(chloroacetyl)-1-(4-methoxybenzene-1-sulfonyl)-N-[(4-methoxyphenyl)methyl]piperazine-2-carboxamide, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: covalent adduct, splicing factor, dbhs family, paraspeckle, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 122841.32

Authors

Bond, C.S.,Marshall, A.C.,Villa Gomez, A.,Hockley, T.K. (deposition date: 2025-03-31, release date: 2025-12-17, Last modification date: 2026-07-01)

Primary citation

Lindsey, G.L.,Hockley, T.K.,Gomez, A.V.,Marshall, A.C.,Brothers, W.R.,Finney, C.T.,Gross, J.,Fox, A.H.,Yeo, G.W.,Melillo, B.,Bond, C.S.,Cravatt, B.F.
Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO.
Cell Chem Biol, 33:256-267.e11, 2026

PubMed 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.

PubMed: 41534524
DOI: 10.1016/j.chembiol.2025.12.010

Experimental method

X-RAY DIFFRACTION (2.52 Å)