Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C

Sackton, KL and Dimova, N and Zeng, X and Tian, W and Zhang, M and Sackton, TB and Meaders, J and Pfaff, KL and Sigoillot, F and Yu, H and Luo, X and King, RW (2014) Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature.

Abstract

Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome. Because blocking mitotic exit is an effective approach for inducing tumour cell death, the APC/C represents a potential novel target for cancer therapy. APC/C activation in mitosis requires binding of Cdc20 (ref. 5), which forms a co-receptor with the APC/C to recognize substrates containing a destruction box (D-box). Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identify a small molecule, called apcin (APC inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-l-arginine methyl ester, a small molecule that blocks the APC/C-Cdc20 interaction. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine

Item Type: Article
Additional Information: NIBR author: Sigoillot, F institute: NIBR- address only contributor address:
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23445

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.