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| | ==Crystal structure of the catalytic domain of PPIP5K2 in complex with AMPPNP and 5-PA-InsP5== | | ==Crystal structure of the catalytic domain of PPIP5K2 in complex with AMPPNP and 5-PA-InsP5== |
| - | <StructureSection load='4nzm' size='340' side='right' caption='[[4nzm]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4nzm' size='340' side='right'caption='[[4nzm]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nzm]] 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=4NZM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NZM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nzm]] 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=4NZM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NZM FirstGlance]. <br> |
| - | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EJ:(2-OXO-2-{[(1S,2R,3S,4S,5R,6S)-2,3,4,5,6-PENTAKIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}ETHYL)PHOSPHONIC+ACID'>0EJ</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene><br> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3t9b|3t9b]], [[4nzo|4nzo]], [[4nzn|4nzn]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EJ:(2-OXO-2-{[(1S,2R,3S,4S,5R,6S)-2,3,4,5,6-PENTAKIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}ETHYL)PHOSPHONIC+ACID'>0EJ</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPIP5K2, HISPPD1, KIAA0433, VIP2 ([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=4nzm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nzm OCA], [https://pdbe.org/4nzm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nzm RCSB], [https://www.ebi.ac.uk/pdbsum/4nzm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nzm ProSAT]</span></td></tr> |
| - | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nzm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nzm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nzm RCSB], [http://www.ebi.ac.uk/pdbsum/4nzm PDBsum]</span></td></tr>
| + | </table> |
| - | <table> | + | == Function == |
| | + | [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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4nzm" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Shears, S B.]] | + | [[Category: Large Structures]] |
| - | [[Category: Wang, H.]] | + | [[Category: Shears SB]] |
| - | [[Category: Atp-grasp fold]] | + | [[Category: Wang H]] |
| - | [[Category: Drug discovery]]
| + | |
| - | [[Category: Enzymology]]
| + | |
| - | [[Category: Inositol pyrophosphate kinase]]
| + | |
| - | [[Category: Inositol pyrophosphate]]
| + | |
| - | [[Category: Kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| 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
Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP-InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design.
Synthetic Inositol Phosphate Analogs Reveal that PPIP5K2 Has a Surface-Mounted Substrate Capture Site that Is a Target for Drug Discovery.,Wang H, Godage HY, Riley AM, Weaver JD, Shears SB, Potter BV Chem Biol. 2014 May 22;21(5):689-99. doi: 10.1016/j.chembiol.2014.03.009. Epub, 2014 Apr 24. PMID:24768307[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
- ↑ Wang H, Godage HY, Riley AM, Weaver JD, Shears SB, Potter BV. Synthetic Inositol Phosphate Analogs Reveal that PPIP5K2 Has a Surface-Mounted Substrate Capture Site that Is a Target for Drug Discovery. Chem Biol. 2014 May 22;21(5):689-99. doi: 10.1016/j.chembiol.2014.03.009. Epub, 2014 Apr 24. PMID:24768307 doi:http://dx.doi.org/10.1016/j.chembiol.2014.03.009
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