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| | <StructureSection load='6m8d' size='340' side='right'caption='[[6m8d]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='6m8d' size='340' side='right'caption='[[6m8d]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6m8d]] 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=6M8D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6M8D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6m8d]] 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=6M8D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M8D FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J8D:5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one'>J8D</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]] 2Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J8D:5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one'>J8D</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=6m8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m8d OCA], [http://pdbe.org/6m8d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6m8d RCSB], [http://www.ebi.ac.uk/pdbsum/6m8d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6m8d 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=6m8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m8d OCA], [https://pdbe.org/6m8d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m8d RCSB], [https://www.ebi.ac.uk/pdbsum/6m8d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m8d 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Shears, S B]] | + | [[Category: Shears SB]] |
| - | [[Category: Wang, H]] | + | [[Category: Wang H]] |
| - | [[Category: Diosmetin]]
| + | |
| - | [[Category: Flavonoid]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Inositol]]
| + | |
| - | [[Category: Inositol polyphosphate]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Natural product]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
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).[1] [2]
Publication Abstract from PubMed
Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 muM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract.
Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis.,Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub , 2019 Jan 25. PMID:30624931[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nalaskowski MM, Deschermeier C, Fanick W, Mayr GW. The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization. Biochem J. 2002 Sep 1;366(Pt 2):549-56. PMID:12027805 doi:http://dx.doi.org/10.1042/BJ20020327
- ↑ Chang SC, Miller AL, Feng Y, Wente SR, Majerus PW. The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase. J Biol Chem. 2002 Nov 15;277(46):43836-43. Epub 2002 Sep 9. PMID:12223481 doi:http://dx.doi.org/10.1074/jbc.M206134200
- ↑ Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub , 2019 Jan 25. PMID:30624931 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01593
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