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| | ==Structure of the CDC25B Phosphatase Catalytic Domain with Bound Ligand== | | ==Structure of the CDC25B Phosphatase Catalytic Domain with Bound Ligand== |
| - | <StructureSection load='4wh7' size='340' side='right' caption='[[4wh7]], [[Resolution|resolution]] 1.62Å' scene=''> | + | <StructureSection load='4wh7' size='340' side='right'caption='[[4wh7]], [[Resolution|resolution]] 1.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wh7]] 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=4WH7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WH7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wh7]] 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=4WH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WH7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8H8:2-FLUORO-4-HYDROXYBENZONITRILE'>8H8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.62Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wh9|4wh9]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8H8:2-FLUORO-4-HYDROXYBENZONITRILE'>8H8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDC25B, CDC25HU2 ([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=4wh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wh7 OCA], [https://pdbe.org/4wh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wh7 RCSB], [https://www.ebi.ac.uk/pdbsum/4wh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wh7 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </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=4wh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wh7 OCA], [http://pdbe.org/4wh7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wh7 RCSB], [http://www.ebi.ac.uk/pdbsum/4wh7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wh7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MPIP2_HUMAN MPIP2_HUMAN]] Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity.<ref>PMID:17332740</ref> | + | [https://www.uniprot.org/uniprot/MPIP2_HUMAN MPIP2_HUMAN] Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity.<ref>PMID:17332740</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wh7" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wh7" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dual specificity phosphatase 3D structures|Dual specificity phosphatase 3D structures]] |
| | + | *[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Borkin, D]] | + | [[Category: Borkin D]] |
| - | [[Category: Cierpicki, T]] | + | [[Category: Cierpicki T]] |
| - | [[Category: Dudkin, S]] | + | [[Category: Dudkin S]] |
| - | [[Category: Grembecka, J]] | + | [[Category: Grembecka J]] |
| - | [[Category: Lund, G L]] | + | [[Category: Lund GL]] |
| - | [[Category: Ni, W]] | + | [[Category: Ni W]] |
| - | [[Category: Fragment]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Phosphatase]]
| + | |
| Structural highlights
Function
MPIP2_HUMAN Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity.[1]
Publication Abstract from PubMed
CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.
Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction.,Lund G, Dudkin S, Borkin D, Ni W, Grembecka J, Cierpicki T ACS Chem Biol. 2014 Dec 1. PMID:25423142[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schmidt A, Durgan J, Magalhaes A, Hall A. Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis. EMBO J. 2007 Mar 21;26(6):1624-36. Epub 2007 Mar 1. PMID:17332740 doi:http://dx.doi.org/10.1038/sj.emboj.7601637
- ↑ Lund G, Dudkin S, Borkin D, Ni W, Grembecka J, Cierpicki T. Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction. ACS Chem Biol. 2014 Dec 1. PMID:25423142 doi:http://dx.doi.org/10.1021/cb500883h
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