|
|
| Line 1: |
Line 1: |
| | + | |
| | ==Protein phosphatase 2A core complex bound to dinophysistoxin-2== | | ==Protein phosphatase 2A core complex bound to dinophysistoxin-2== |
| - | <StructureSection load='3k7w' size='340' side='right' caption='[[3k7w]], [[Resolution|resolution]] 2.96Å' scene=''> | + | <StructureSection load='3k7w' size='340' side='right'caption='[[3k7w]], [[Resolution|resolution]] 2.96Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3k7w]] is a 2 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=3K7W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3K7W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3k7w]] is a 2 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=3K7W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3K7W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XT2:(2R)-2-HYDROXY-3-[(2S,5R,6R,8S)-5-HYDROXY-8-{(1R,2E)-3-[(2R,4AR,5R,6S,8R,8AS)-8-HYDROXY-6-{(1S,3S)-1-HYDROXY-3-[(2S,6R,11S)-11-METHYL-1,7-DIOXASPIRO[5.5]UNDEC-2-YL]BUTYL}-7-METHYLIDENEOCTAHYDRO-3H,3H-SPIRO[FURAN-2,2-PYRANO[3,2-B]PYRAN]-5-YL]-1-METHYLPROP-2-EN-1-YL}-10-METHYL-1,7-DIOXASPIRO[5.5]UNDEC-10-EN-2-YL]-2-METHYLPROPANOIC+ACID'>XT2</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]] 2.96Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ie4|2ie4]], [[3k7v|3k7v]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XT2:(2R)-2-HYDROXY-3-[(2S,5R,6R,8S)-5-HYDROXY-8-{(1R,2E)-3-[(2R,4AR,5R,6S,8R,8AS)-8-HYDROXY-6-{(1S,3S)-1-HYDROXY-3-[(2S,6R,11S)-11-METHYL-1,7-DIOXASPIRO[5.5]UNDEC-2-YL]BUTYL}-7-METHYLIDENEOCTAHYDRO-3H,3H-SPIRO[FURAN-2,2-PYRANO[3,2-B]PYRAN]-5-YL]-1-METHYLPROP-2-EN-1-YL}-10-METHYL-1,7-DIOXASPIRO[5.5]UNDEC-10-EN-2-YL]-2-METHYLPROPANOIC+ACID'>XT2</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPP2R1A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PPP2CA ([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=3k7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k7w OCA], [https://pdbe.org/3k7w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3k7w RCSB], [https://www.ebi.ac.uk/pdbsum/3k7w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3k7w 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/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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3k7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k7w OCA], [http://pdbe.org/3k7w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3k7w RCSB], [http://www.ebi.ac.uk/pdbsum/3k7w PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/2AAA_HUMAN 2AAA_HUMAN]] The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis.<ref>PMID:16580887</ref> [[http://www.uniprot.org/uniprot/PP2AA_HUMAN PP2AA_HUMAN]] PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGOL2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.<ref>PMID:9920888</ref> <ref>PMID:10801873</ref> <ref>PMID:22613722</ref> | + | [https://www.uniprot.org/uniprot/2AAA_HUMAN 2AAA_HUMAN] The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis.<ref>PMID:16580887</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k7/3k7w_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k7/3k7w_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| Line 32: |
Line 31: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Serine/threonine protein phosphatase|Serine/threonine protein phosphatase]] | + | *[[Protein phosphatase 3D structures|Protein phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Phosphoprotein phosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Huhn, J]] | + | [[Category: Huhn J]] |
| - | [[Category: Jeffrey, P D]] | + | [[Category: Jeffrey PD]] |
| - | [[Category: Shi, Y]] | + | [[Category: Shi Y]] |
| - | [[Category: Centromere]]
| + | |
| - | [[Category: Cytoskeleton]]
| + | |
| - | [[Category: Heat repeat]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Ligand specificity]]
| + | |
| - | [[Category: Manganese]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Methylation]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphatase]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protein phosphatase]]
| + | |
| - | [[Category: Protein-protein complex]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Signaling protein-hydrolase complex]]
| + | |
| Structural highlights
Function
2AAA_HUMAN The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are algal toxins that can accumulate in shellfish and cause diarrhetic shellfish poisoning. Recent studies indicate that DTX-2 is about half as toxic and has about half the affinity for protein phosphatase 2A (PP2A) as OA. NMR structural studies showed that DTX-1 possessed an equatorial 35-methyl group but that DTX-2 had an axial 35-methyl group. Molecular modeling studies indicated that an axial 35-methyl could exhibit unfavorable interactions in the PP2A binding site, and this has been proposed as the reason for the reduced toxicity of DTX-2. Statistical analyses of published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower, than for OA. We obtained X-ray crystal structures of DTX-1 and DTX-2 bound to PP2A. The crystal structures independently confirm the C-35 stereochemistries determined in the earlier NMR study. The structure for the DTX-1 complex was virtually identical to that of the OA-PP2A complex, except for the presence of the equatorial 35-methyl on the ligand. The favorable placement of the equatorial 35-methyl group of DTX-1 against the aromatic pi-bonds of His191 may account for the increased affinity of PP2A toward DTX-1. In contrast, the axial 35-methyl of DTX-2 caused the side chain of His191 to rotate 140 degrees so that it pointed toward the solvent, thereby opening one end of the hydrophobic binding cage. This rearrangement to accommodate the unfavorable interaction from the axial 35-methyl of DTX-2 reduces the binding energy and appears to be responsible for the reduced affinity of PP2A for DTX-2. These results highlight the potential of molecular modeling studies for understanding the relative toxicity of analogues once the binding site at the molecular target has been properly characterized.
A structural basis for the reduced toxicity of dinophysistoxin-2.,Huhn J, Jeffrey PD, Larsen K, Rundberget T, Rise F, Cox NR, Arcus V, Shi Y, Miles CO Chem Res Toxicol. 2009 Nov;22(11):1782-6. PMID:19916524[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tang Z, Shu H, Qi W, Mahmood NA, Mumby MC, Yu H. PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev Cell. 2006 May;10(5):575-85. Epub 2006 Mar 30. PMID:16580887 doi:10.1016/j.devcel.2006.03.010
- ↑ Huhn J, Jeffrey PD, Larsen K, Rundberget T, Rise F, Cox NR, Arcus V, Shi Y, Miles CO. A structural basis for the reduced toxicity of dinophysistoxin-2. Chem Res Toxicol. 2009 Nov;22(11):1782-6. PMID:19916524 doi:10.1021/tx9001622
|
