Suramin inhibits cullin-RING E3 ubiquitin ligases

Abstract

Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3′s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a smallmolecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.protein degradation | K48-polyubiquitination | E3 ligase | E2 enzyme | suramin

Small‐Molecule Inhibitors of the Tumor Suppressor Fhit

“…Cu 2+ and Zn 2+ , however, inhibit Fhit rather unspecifically because they have many other functions and targets within cells. Suramin also inhibits several different classes of enzymes . Reported IC 50 values of ZnCl 2 and suramin towards Fhit are in the micromolar rather than the nanomolar range .…”

Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

“…For example, downregulation of ubiquitin‐conjugating enzyme E2 R1 (CDC34) inhibits the degradation of cyclin‐dependent kinase inhibitor 1B (CDKN1B or p27 Kip1 ) by reducing its ubiquitination and thus prevents cellular proliferation , although both the enzymatic and nonenzymatic functions of CDC34 may play a role in regulating proliferation of a specific cell line . Suramin, a polysulfonated naphthylurea, disrupts the interaction between cullin‐1 and CDC34 and thus inhibits the activity of CRL E3 ligase complexes . The low molecular weight compound CC0651 and its analogs cause the accumulation of p27 Kip1 by interfering with the transfer of ubiquitin to the lysine residues of substrates through allosteric inhibition of CDC34 and thereby inhibit the proliferation of human cancer cells .…”

COP9 signalosome subunits protect Capicua from MAPK-dependent and -independent mechanisms of degradation

“…The ubiquitin modification itself may be sufficient to block Cic activity even before its degradation; the moderate reduction in Cic protein we observed in CSN mutant cells is similar to the reduction in cic heterozygous cells, which is not sufficient for ectopic aos expression (Fores et al, 2015). These findings suggest that drugs that target CRLs, such as MLN4924 or suramin, might be useful in treating cancers for which CIC is a suppressor of growth or metastasis (Bettegowda et al, 2011;Choi et al, 2015;Dissanayake et al, 2011;Nawrocki et al, 2012;Okimoto et al, 2016;Wu et al, 2016). Conversely, drugs that antagonize the CSN might help reduce the accumulation of toxic Cic-Ataxin complexes in spinocerebellar ataxia (Lam et al, 2006;Lasagna-Reeves et al, 2015).…”