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| | ==Crystal structure of Cdc20 and apcin complex== | | ==Crystal structure of Cdc20 and apcin complex== |
| - | <StructureSection load='4n14' size='340' side='right' caption='[[4n14]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4n14' size='340' side='right'caption='[[4n14]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4n14]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N14 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N14 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N14 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=WR7:2-(2-METHYL-5-NITRO-1H-IMIDAZOL-1-YL)ETHYL+[(1R)-2,2,2-TRICHLORO-1-(PYRIMIDIN-2-YLAMINO)ETHYL]CARBAMATE'>WR7</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gga|4gga]], [[4ggc|4ggc]], [[4ggd|4ggd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WR7:2-(2-METHYL-5-NITRO-1H-IMIDAZOL-1-YL)ETHYL+[(1R)-2,2,2-TRICHLORO-1-(PYRIMIDIN-2-YLAMINO)ETHYL]CARBAMATE'>WR7</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDC20 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n14 OCA], [https://pdbe.org/4n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n14 RCSB], [https://www.ebi.ac.uk/pdbsum/4n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n14 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n14 OCA], [http://pdbe.org/4n14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4n14 RCSB], [http://www.ebi.ac.uk/pdbsum/4n14 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4n14 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CDC20_HUMAN CDC20_HUMAN]] Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation.<ref>PMID:9811605</ref> <ref>PMID:9734353</ref> <ref>PMID:9637688</ref> | + | [https://www.uniprot.org/uniprot/CDC20_HUMAN CDC20_HUMAN] Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation.<ref>PMID:9811605</ref> <ref>PMID:9734353</ref> <ref>PMID:9637688</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | 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.
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| - | Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C.,Sackton KL, Dimova N, Zeng X, Tian W, Zhang M, Sackton TB, Meaders J, Pfaff KL, Sigoillot F, Yu H, Luo X, King RW Nature. 2014 Aug 24. doi: 10.1038/nature13660. PMID:25156254<ref>PMID:25156254</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4n14" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Luo, X]] | + | [[Category: Large Structures]] |
| - | [[Category: Tian, W]] | + | [[Category: Luo X]] |
| - | [[Category: Yu, H]] | + | [[Category: Tian W]] |
| - | [[Category: Cell cycle]] | + | [[Category: Yu H]] |
| - | [[Category: Cell cycle-cell cycle inhibitor complex]]
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| - | [[Category: Mitosis]]
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| - | [[Category: Securin]]
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| - | [[Category: Ubiquitination]]
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| - | [[Category: Wd40]]
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