4N14

Crystal structure of Cdc20 and apcin complex

Summary for 4N14

• Entry DOI: 10.2210/pdb4n14/pdb
• Related: 4GGA 4GGC 4GGD
• Descriptor: Cell division cycle protein 20 homolog, 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl [(1R)-2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl]carbamate (3 entities in total)
• Functional Keywords: cell cycle, mitosis, securin, ubiquitination, wd40, cell cycle-cell cycle inhibitor complex, cell cycle/cell cycle inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : Q12834
• Total number of polymer chains: 1
• Total formula weight: 34876.21

Authors

Luo, X.,Tian, W.,Yu, H. (deposition date: 2013-10-03, release date: 2014-08-20, Last modification date: 2024-02-28)

Primary citation

Sackton, K.L.,Dimova, N.,Zeng, X.,Tian, W.,Zhang, M.,Sackton, T.B.,Meaders, J.,Pfaff, K.L.,Sigoillot, F.,Yu, H.,Luo, X.,King, R.W.
Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C.
Nature, 514:646-649, 2014

PubMed 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.

PubMed: 25156254
DOI: 10.1038/nature13660

Experimental method

X-RAY DIFFRACTION (2.1 Å)