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Synergistic Blockade of Mitotic Exit by Two Chemical Inhibitors of the APC/C

Synergistic Blockade of Mitotic Exit by Two Chemical Inhibitors of the APC/C

Katharine L Sackton, Nevena Dimova, Xing Zeng, Wei Tian, Mengmeng Zhang, Timothy B Sackton, Johnathan Meaders, Kathleen L Pfaff, Frederic Sigoillot, Hongtao Yu, Xuelian Luo, Randall W King

Nature. 2014 Oct 30;514(7524):646-9.

PMID: 25156254

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP300815047	Apcin		300815-04-7	Price

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