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

Research output: Contribution to journalArticle

83 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)646-649
Number of pages4
JournalNature
Volume514
Issue number7524
DOIs
StatePublished - Aug 14 2014

Fingerprint

Anaphase-Promoting Complex-Cyclosome
Proteins
Ubiquitin
Securin
Cyclin B1
Anaphase
Ubiquitination
Protein Subunits
Protein Transport
Proteasome Endopeptidase Complex
Metaphase
Ligases
Mitosis
Proteolysis
Neoplasms
Cell Death

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Sackton, K. L., Dimova, N., Zeng, X., Tian, W., Zhang, M., Sackton, T. B., ... King, R. W. (2014). Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature, 514(7524), 646-649. https://doi.org/10.1038/nature13660

Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. / Sackton, Katharine L.; Dimova, Nevena; Zeng, Xing; Tian, Wei; Zhang, Mengmeng; Sackton, Timothy B.; Meaders, Johnathan; Pfaff, Kathleen L.; Sigoillot, Frederic; Yu, Hongtao; Luo, Xuelian; King, Randall W.

In: Nature, Vol. 514, No. 7524, 14.08.2014, p. 646-649.

Research output: Contribution to journalArticle

Sackton, KL, Dimova, N, Zeng, X, Tian, W, Zhang, M, Sackton, TB, Meaders, J, Pfaff, KL, Sigoillot, F, Yu, H, Luo, X & King, RW 2014, 'Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C', Nature, vol. 514, no. 7524, pp. 646-649. https://doi.org/10.1038/nature13660
Sackton KL, Dimova N, Zeng X, Tian W, Zhang M, Sackton TB et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature. 2014 Aug 14;514(7524):646-649. https://doi.org/10.1038/nature13660
Sackton, Katharine L. ; Dimova, Nevena ; Zeng, Xing ; Tian, Wei ; Zhang, Mengmeng ; Sackton, Timothy B. ; Meaders, Johnathan ; Pfaff, Kathleen L. ; Sigoillot, Frederic ; Yu, Hongtao ; Luo, Xuelian ; King, Randall W. / Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. In: Nature. 2014 ; Vol. 514, No. 7524. pp. 646-649.
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