title: E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin.
abstract: Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
authors: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
authors: Hao
authors: H
authors: Huang
authors: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
authors: Derek F
authors: DF
authors: Ceccarelli
authors: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
authors: Stephen
authors: S
authors: Orlicky
authors: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.
authors: Daniel J
authors: DJ
authors: St-Cyr
authors: Department of Chemistry, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV, 89154.
authors: Amy
authors: A
authors: Ziemba
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors: Pankaj
authors: P
authors: Garg
authors: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.
authors: Serge
authors: S
authors: Plamondon
authors: School of Biological Sciences, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR United Kingdom.
authors: Manfred
authors: M
authors: Auer
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors: Sachdev
authors: S
authors: Sidhu
authors: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.|Department of Chemistry, University of Montreal, Montreal, Québec H3C 3J7, Canada.
authors: Anne
authors: A
authors: Marinier
authors: Department of Chemistry, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV, 89154.
authors: Gary
authors: G
authors: Kleiger
authors: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.|Department of Medicine, University of Montreal, Montreal, Québec H3C 3J7, Canada.
authors: Mike
authors: M
authors: Tyers
authors: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Frank
authors: F
authors: Sicheri
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D055550:Protein Stability / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D025801:Ubiquitin / Q000737:chemistry*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors*
chemical_list: C560583:5-(3',5'-dichlorobiphenyl-4-yl)-2,3-dihydroxy-4-(2-methoxyacetamido)pentanoic acid; D000596:Amino Acids; D001713:Biphenyl Compounds; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes