|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5wg8' size='340' side='right'caption='[[5wg8]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='5wg8' size='340' side='right'caption='[[5wg8]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5wg8]] 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=5WG8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WG8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5wg8]] 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=5WG8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WG8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LB1:(1S,2R,3S,4R)-3-(4-methylpiperazine-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic+acid'>LB1</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</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]] 1.65Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPP5C, PPP5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LB1:(1S,2R,3S,4R)-3-(4-methylpiperazine-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic+acid'>LB1</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </span></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=5wg8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg8 OCA], [https://pdbe.org/5wg8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wg8 RCSB], [https://www.ebi.ac.uk/pdbsum/5wg8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg8 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=5wg8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg8 OCA], [http://pdbe.org/5wg8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wg8 RCSB], [http://www.ebi.ac.uk/pdbsum/5wg8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PPP5_HUMAN PPP5_HUMAN]] May play a role in the regulation of RNA biogenesis and/or mitosis. In vitro, dephosphorylates serine residues of skeletal muscle phosphorylase and histone H1. | + | [https://www.uniprot.org/uniprot/PPP5_HUMAN PPP5_HUMAN] May play a role in the regulation of RNA biogenesis and/or mitosis. In vitro, dephosphorylates serine residues of skeletal muscle phosphorylase and histone H1. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5wg8" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5wg8" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Protein phosphatase 3D structures|Protein phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphoprotein phosphatase]] | + | [[Category: D'Arcy BM]] |
| - | [[Category: Arcy, B M.D]]
| + | [[Category: Honkanen RE]] |
| - | [[Category: Honkanen, R E]] | + | [[Category: Prakash A]] |
| - | [[Category: Prakash, A]] | + | [[Category: Swingle MR]] |
| - | [[Category: Swingle, M R]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase inhibitor]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| Structural highlights
Function
PPP5_HUMAN May play a role in the regulation of RNA biogenesis and/or mitosis. In vitro, dephosphorylates serine residues of skeletal muscle phosphorylase and histone H1.
Publication Abstract from PubMed
LB-100 is an experimental cancer therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/PPP2CA:PPP2CB), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A in vitro, in cultured cells, or in animals. Rather, the premise for LB-100 targeting PP2AC is derived from studies that measure phosphate released from a phosphopeptide (K-R-pT-I-R-R) or inferred from the ability of LB-100 to mimic activity previously reported to result from the inhibition of PP2AC by other means. PP2AC and PPP5C share a common catalytic mechanism. Here, we demonstrate that the phosphopeptide used to ascribe LB-100 specificity for PP2A is also a substrate for PPP5C. Inhibition assays using purified enzymes demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C. The structure of PPP5C cocrystallized with LB-100 was solved to a resolution of 1.65A, revealing that the 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with the metal ions and key residues that are conserved in both PP2AC and PPP5C. Cell-based studies revealed some known actions of LB-100 are mimicked by the genetic disruption of PPP5C These data demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C and suggest that the observed antitumor activity might be due to an additive effect achieved by suppressing both PP2A and PPP5C.
The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C.,D'Arcy BM, Swingle MR, Papke CM, Abney KA, Bouska ES, Prakash A, Honkanen RE Mol Cancer Ther. 2019 Mar;18(3):556-566. doi: 10.1158/1535-7163.MCT-17-1143. Epub, 2019 Jan 24. PMID:30679389[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ D'Arcy BM, Swingle MR, Papke CM, Abney KA, Bouska ES, Prakash A, Honkanen RE. The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C. Mol Cancer Ther. 2019 Mar;18(3):556-566. doi: 10.1158/1535-7163.MCT-17-1143. Epub, 2019 Jan 24. PMID:30679389 doi:http://dx.doi.org/10.1158/1535-7163.MCT-17-1143
|
