Ubiquitination of a small molecule

ABSTRACT: Ubiquitin is a small, highly conserved protein that acts as a post-translational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasomal. Here, we report a novel small molecule from a diversity- oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of unproductive ubiquitin monomer and polyubiquitin chains and broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent upon two homologous E3 ubiquitin ligases, RNF19A and RNF19B. Our finding opens a possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule, and more broadly raises the potential for post- translational modification in trans.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Dylan Mitchell  

LAB HEAD: Dylan Mitchell

PROVIDER: PXD065168 | Pride | 2025-09-11

REPOSITORIES: Pride