title: 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 small-molecule 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.
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Chong
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang, China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, 221002, China;
authors.forename: Jin
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London N6A 5C1, ON, Canada;
authors.forename: Donald E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Kevin
authors.initials: K
authors.lastname: Ching
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Chan
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195;
authors.forename: Haibin
authors.initials: H
authors.lastname: Miao
authors.affiliation: Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
authors.forename: Inger
authors.initials: I
authors.lastname: Tappin
authors.affiliation: Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; j-hurwitz@ski.mskcc.org zhen-qiang.pan@mssm.edu.
authors.forename: Jerard
authors.initials: J
authors.lastname: Hurwitz
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195;
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London N6A 5C1, ON, Canada;
authors.forename: Gary S
authors.initials: GS
authors.lastname: Shaw
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang, China; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Regenerative Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Dan P
authors.initials: DP
authors.lastname: Felsenfeld
authors.affiliation: Department of Structural and Chemical Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sanchez
authors.affiliation: Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, 221002, China;
authors.forename: Jun-Nian
authors.initials: JN
authors.lastname: Zheng
authors.affiliation: Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, 221002, China; j-hurwitz@ski.mskcc.org zhen-qiang.pan@mssm.edu.
authors.forename: Zhen-Qiang
authors.initials: ZQ
authors.lastname: Pan
mesh_terms: D008025:Ligases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013498:Suramin / Q000494:pharmacology*
chemical_list: D013498:Suramin; D008025:Ligases
keywords: E2 enzyme; E3 ligase; K48-polyubiquitination; protein degradation; suramin