2. Academic Validation
  3. E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin

E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin

  • Nat Chem Biol. 2014 Feb;10(2):156-163. doi: 10.1038/nchembio.1412.
Hao Huang  # 1,  Derek F Ceccarelli  # 1,  Stephen Orlicky  # 1,  Daniel J St-Cyr 2,  Amy Ziemba 3,  Pankaj Garg 4 5,  Serge Plamondon 2,  Manfred Auer 6,  Sachdev Sidhu 4 5,  Anne Marinier 2 7,  Gary Kleiger 3,  Mike Tyers 2 8,  Frank Sicheri 1 4
Affiliations

Affiliations

  • 1 Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
  • 2 Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Québec H3C 3J7, Canada.
  • 3 Department of Chemistry, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV, 89154.
  • 4 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 5 Banting and Best Department of Medical Research, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
  • 6 School of Biological Sciences, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR United Kingdom.
  • 7 Department of Chemistry, University of Montreal, Montreal, Québec H3C 3J7, Canada.
  • 8 Department of Medicine, University of Montreal, Montreal, Québec H3C 3J7, Canada.
  • # Contributed equally.
PMID: 24316736 DOI: 10.1038/nchembio.1412
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.

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