期刊
NATURE
卷 514, 期 7524, 页码 646-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13660
关键词
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资金
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- National Institutes of Health [GM085004, GM066492]
- Lynch Foundation
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(1,2). Because blocking mitotic exit is an effective approach for inducing tumour cell death(3,4), the APC/Crepresents 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)(6-14). 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(15,16). This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.
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