3RZ3

Human Cdc34 E2 in complex with CC0651 inhibitor

Summary for 3RZ3

• Entry DOI: 10.2210/pdb3rz3/pdb
• Related: 2OB4
• Descriptor: Ubiquitin-conjugating enzyme E2 R1, 4,5-dideoxy-5-(3',5'-dichlorobiphenyl-4-yl)-4-[(methoxyacetyl)amino]-L-arabinonic acid (3 entities in total)
• Functional Keywords: ubiquitin conjugating enzyme domain, e2 domain, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49427
• Total number of polymer chains: 4
• Total formula weight: 84807.14

Authors

Ceccarelli, D.F.,Webb, D.R.,Sicheri, F. (deposition date: 2011-05-11, release date: 2011-07-06, Last modification date: 2024-11-06)

Primary citation

Ceccarelli, D.F.,Tang, X.,Pelletier, B.,Orlicky, S.,Xie, W.,Plantevin, V.,Neculai, D.,Chou, Y.C.,Ogunjimi, A.,Al-Hakim, A.,Varelas, X.,Koszela, J.,Wasney, G.A.,Vedadi, M.,Dhe-Paganon, S.,Cox, S.,Xu, S.,Lopez-Girona, A.,Mercurio, F.,Wrana, J.,Durocher, D.,Meloche, S.,Webb, D.R.,Tyers, M.,Sicheri, F.
An allosteric inhibitor of the human cdc34 ubiquitin conjugating enzyme
Cell(Cambridge,Mass.), 145:1075-1087, 2011

PubMed 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.

PubMed: 21683433
DOI: 10.1016/j.cell.2011.05.039

Experimental method

X-RAY DIFFRACTION (2.3 Å)