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| | ==Crystal structure of the core catalytic domain of human inositol phosphate multikinase soaked with C4-analogue of PtdIns(4,5)P2 and ADP== | | ==Crystal structure of the core catalytic domain of human inositol phosphate multikinase soaked with C4-analogue of PtdIns(4,5)P2 and ADP== |
| - | <StructureSection load='5w2i' size='340' side='right' caption='[[5w2i]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='5w2i' size='340' side='right'caption='[[5w2i]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5w2i]] 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=5W2I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W2I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5w2i]] 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=5W2I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W2I 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=I3P:D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE'>I3P</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]] 1.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5w2g|5w2g]], [[5w2h|5w2h]]</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=I3P:D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE'>I3P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IPMK, IMPK ([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=5w2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2i OCA], [https://pdbe.org/5w2i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w2i RCSB], [https://www.ebi.ac.uk/pdbsum/5w2i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2i 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/Inositol-polyphosphate_multikinase Inositol-polyphosphate multikinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.151 2.7.1.151] </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=5w2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2i OCA], [http://pdbe.org/5w2i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w2i RCSB], [http://www.ebi.ac.uk/pdbsum/5w2i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IPMK_HUMAN IPMK_HUMAN]] Inositol phosphate kinase with a broad substrate specificity. Has a preference for inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4).<ref>PMID:12027805</ref> <ref>PMID:12223481</ref> | + | [https://www.uniprot.org/uniprot/IPMK_HUMAN IPMK_HUMAN] Inositol phosphate kinase with a broad substrate specificity. Has a preference for inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4).<ref>PMID:12027805</ref> <ref>PMID:12223481</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Human inositol phosphate multikinase (HsIPMK) critically contributes to intracellular signaling through its inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) 3-kinase and phosphatidylinositol- 4,5-bisphosphate (PtdIns(4,5)P2) 3-kinase activities. This catalytic profile is not conserved; orthologs from Arabidopsis thaliana and Saccharomyces cerevisiae are predominantly Ins(1,4,5)P3 6-kinases, and the plant enzyme cannot phosphorylate PtdIns(4,5)P2. Therefore, crystallographic analysis of the yeast and plant enzymes, without bound inositol phosphates, do not structurally rationalize HsIPMK activities. Here, we present 1.6 A resolution crystal structures of HsIPMK in complex with either Ins(1,4,5)P3 or PtdIns(4,5)P2. The Ins(1,4,5)P3 headgroup of PtdIns(4,5)P2 binds in precisely the same orientation as free Ins(1,4,5)P3 itself, indicative of evolutionary optimization of 3- kinase activities against both substrates. We report on nucleotide binding between the separate N- and C-lobes of HsIPMK. The N-lobe exhibits a remarkable degree of conservation with protein kinase A (root mean square deviation = 1.8 A), indicating common ancestry. We also describe structural features unique to HsIPMK. First, we observed a constrained, horseshoe-shaped substrate pocket, formed from an alpha-helix, a 310 helix, and a recently evolved tri-proline loop. We further found HsIPMK activities rely on a preponderance of Gln residues, in contrast to the larger Lys and Arg residues in yeast and plant orthologs. These conclusions are supported by analyzing 14 single-site HsIPMK mutants, some of which differentially affect 3-kinase and 6- kinase activities. Overall, we structurally rationalize phosphorylation of Ins(1,4,5)P3 and PtdIns(4,5)P2 by HsIPMK.
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| - | Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities.,Wang H, Shears SB J Biol Chem. 2017 Sep 7. pii: jbc.M117.801845. doi: 10.1074/jbc.M117.801845. PMID:28882892<ref>PMID:28882892</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5w2i" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Inositol-polyphosphate multikinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Shears, S B]] | + | [[Category: Shears SB]] |
| - | [[Category: Wang, H]] | + | [[Category: Wang H]] |
| - | [[Category: Inositol]]
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| - | [[Category: Inositol polyphosphate]]
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| - | [[Category: Kinase]]
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| - | [[Category: Phosphatidylinositol]]
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| - | [[Category: Specificity]]
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| - | [[Category: Transferase]]
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