title: An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme.
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.
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada.
authors.forename: Derek F
authors.initials: DF
authors.lastname: Ceccarelli
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Tang
authors.forename: Benoit
authors.initials: B
authors.lastname: Pelletier
authors.forename: Stephen
authors.initials: S
authors.lastname: Orlicky
authors.forename: Weilin
authors.initials: W
authors.lastname: Xie
authors.forename: Veronique
authors.initials: V
authors.lastname: Plantevin
authors.forename: Dante
authors.initials: D
authors.lastname: Neculai
authors.forename: Yang-Chieh
authors.initials: YC
authors.lastname: Chou
authors.forename: Abiodun
authors.initials: A
authors.lastname: Ogunjimi
authors.forename: Abdallah
authors.initials: A
authors.lastname: Al-Hakim
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.forename: Joanna
authors.initials: J
authors.lastname: Koszela
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.forename: Sarah
authors.initials: S
authors.lastname: Cox
authors.forename: Shuichan
authors.initials: S
authors.lastname: Xu
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.forename: Frank
authors.initials: F
authors.lastname: Mercurio
authors.forename: Jeff
authors.initials: J
authors.lastname: Wrana
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: David R
authors.initials: DR
authors.lastname: Webb
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.forename: Frank
authors.initials: F
authors.lastname: Sicheri
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000494:pharmacology*; D064173:Anaphase-Promoting Complex-Cyclosome; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: C560583:5-(3',5'-dichlorobiphenyl-4-yl)-2,3-dihydroxy-4-(2-methoxyacetamido)pentanoic acid; D000596:Amino Acids; D001713:Biphenyl Compounds; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome