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An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme |
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| Authors: | Ceccarelli Derek F Tang Xiaojing Pelletier Benoit Orlicky Stephen Xie Weilin Plantevin Veronique Neculai Dante Chou Yang-Chieh Ogunjimi Abiodun Al-Hakim Abdallah Varelas Xaralabos Koszela Joanna Wasney Gregory A Vedadi Masoud Dhe-Paganon Sirano Cox Sarah Xu Shuichan Lopez-Girona Antonia Mercurio Frank Wrana Jeff Durocher Daniel Meloche Sylvain Webb David R Tyers Mike Sicheri Frank |
| Affiliation: | 1 Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada 2 Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec H3C3J7, Canada 3 Program of Molecular Biology and Department of Pharmacology, Université de Montréal, Montreal, Quebec H3C3J7, Canada 4 Structural Genomics Consortium, Suite 700, MaRS South Tower, 101 College Street, Toronto, Ontario M5G1L7, Canada 5 Celgene Signal Research Division, 4550 Towne Centre Court, San Diego, CA 92121-1900, USA 6 Wellcome Trust Centre for Cell Biology, King's Buildings, Mayfield Road, University of Edinburgh, Edinburgh, Scotland EH93JR, UK 7 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S1A8, Canada |
| Abstract: | In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS. |
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