4MDK

Cdc34-ubiquitin-CC0651 complex

Summary for 4MDK

• Entry DOI: 10.2210/pdb4mdk/pdb
• Descriptor: Ubiquitin-conjugating enzyme E2 R1, Ubiquitin, 4,5-dideoxy-5-(3',5'-dichlorobiphenyl-4-yl)-4-[(methoxyacetyl)amino]-L-arabinonic acid, ... (4 entities in total)
• Functional Keywords: ubiquitin conjugating enzyme domain, e2 ligase inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P49427; Ubiquitin: Cytoplasm (By similarity): P0CG48
• Total number of polymer chains: 8
• Total formula weight: 119342.64

Authors

Ceccarelli, D.F.,Orlicky, S.,Tyers, M.,Sicheri, F. (deposition date: 2013-08-22, release date: 2013-12-11, Last modification date: 2023-09-20)

Primary citation

Huang, H.,Ceccarelli, D.F.,Orlicky, S.,St-Cyr, D.J.,Ziemba, A.,Garg, P.,Plamondon, S.,Auer, M.,Sidhu, S.,Marinier, A.,Kleiger, G.,Tyers, M.,Sicheri, F.
E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin.
Nat.Chem.Biol., 10:156-163, 2014

PubMed 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.

PubMed: 24316736
DOI: 10.1038/nchembio.1412

Experimental method

X-RAY DIFFRACTION (2.6095 Å)