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| | ==Crystal structure of the catalytic domain of human diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) in complex with ADP and synthetic 1,5-(PP)2-IP4 (1,5-IP8)== | | ==Crystal structure of the catalytic domain of human diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) in complex with ADP and synthetic 1,5-(PP)2-IP4 (1,5-IP8)== |
| - | <StructureSection load='4q4c' size='340' side='right' caption='[[4q4c]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4q4c' size='340' side='right'caption='[[4q4c]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4q4c]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q4C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q4C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4q4c]] 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=4Q4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q4C FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=I8P:(1R,3S,4R,5S,6R)-2,4,5,6-TETRAKIS(PHOSPHONOOXY)CYCLOHEXANE-1,3-DIYL+BIS[TRIHYDROGEN+(DIPHOSPHATE)]'>I8P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4q4d|4q4d]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=I8P:(1R,3S,4R,5S,6R)-2,4,5,6-TETRAKIS(PHOSPHONOOXY)CYCLOHEXANE-1,3-DIYL+BIS[TRIHYDROGEN+(DIPHOSPHATE)]'>I8P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=4q4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q4c OCA], [http://pdbe.org/4q4c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q4c RCSB], [http://www.ebi.ac.uk/pdbsum/4q4c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q4c ProSAT]</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=4q4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q4c OCA], [https://pdbe.org/4q4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q4c RCSB], [https://www.ebi.ac.uk/pdbsum/4q4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q4c ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VIP2_HUMAN VIP2_HUMAN]] Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at positions 1 or 3 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates at position 1 or 3 PP-InsP5, produced by IP6Ks from InsP6, to produce (PP)2-InsP4.<ref>PMID:17690096</ref> <ref>PMID:17702752</ref> | + | [https://www.uniprot.org/uniprot/VIP2_HUMAN VIP2_HUMAN] Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at positions 1 or 3 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates at position 1 or 3 PP-InsP5, produced by IP6Ks from InsP6, to produce (PP)2-InsP4.<ref>PMID:17690096</ref> <ref>PMID:17702752</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Shears, S B]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Wang, H]] | + | [[Category: Large Structures]] |
| - | [[Category: Enantiomer]] | + | [[Category: Shears SB]] |
| - | [[Category: Inositol pyrophosphate]] | + | [[Category: Wang H]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Synthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
VIP2_HUMAN Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at positions 1 or 3 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates at position 1 or 3 PP-InsP5, produced by IP6Ks from InsP6, to produce (PP)2-InsP4.[1] [2]
Publication Abstract from PubMed
The ubiquitous mammalian signaling molecule bis-diphosphoinositol tetrakisphosphate (1,5-(PP)2 -myo-InsP4 , or InsP8 ) displays the most congested three-dimensional array of phosphate groups found in nature. The high charge density, the accumulation of unstable P-anhydrides and P-esters, the lack of UV absorbance, and low levels of optical rotation constitute severe obstacles to its synthesis, characterization, and purification. Herein, we describe the first procedure for the synthesis of enantiopure 1,5-(PP)2 -myo-InsP4 and 3,5-(PP)2 -myo-InsP4 utilizing a C2 -symmetric P-amidite for desymmetrization and concomitant phosphitylation followed by a one-pot bidirectional P-anhydride-forming reaction that combines sixteen chemical transformations with high efficiency. The configuration of these materials is unambiguously shown by subsequent X-ray analyses of both enantiomers after being individually soaked into crystals of the kinase domain of human diphosphoinositol pentakisphosphate kinase 2.
Synthesis of Densely Phosphorylated Bis-1,5-Diphospho-myo-Inositol Tetrakisphosphate and its Enantiomer by Bidirectional P-Anhydride Formation.,Capolicchio S, Wang H, Thakor DT, Shears SB, Jessen HJ Angew Chem Int Ed Engl. 2014 Jul 14. doi: 10.1002/anie.201404398. PMID:25044992[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fridy PC, Otto JC, Dollins DE, York JD. Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases. J Biol Chem. 2007 Oct 19;282(42):30754-62. Epub 2007 Aug 9. PMID:17690096 doi:http://dx.doi.org/M704656200
- ↑ Choi JH, Williams J, Cho J, Falck JR, Shears SB. Purification, sequencing, and molecular identification of a mammalian PP-InsP5 kinase that is activated when cells are exposed to hyperosmotic stress. J Biol Chem. 2007 Oct 19;282(42):30763-75. Epub 2007 Aug 16. PMID:17702752 doi:http://dx.doi.org/M704655200
- ↑ Capolicchio S, Wang H, Thakor DT, Shears SB, Jessen HJ. Synthesis of Densely Phosphorylated Bis-1,5-Diphospho-myo-Inositol Tetrakisphosphate and its Enantiomer by Bidirectional P-Anhydride Formation. Angew Chem Int Ed Engl. 2014 Jul 14. doi: 10.1002/anie.201404398. PMID:25044992 doi:http://dx.doi.org/10.1002/anie.201404398
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