View source for 8omi


==Crystal structure of the inositol hexakisphosphate kinase EhIP6KA M85 variant in complex with ATP and Mg2+==
<StructureSection load='8omi' size='340' side='right'caption='[[8omi]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8omi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Entamoeba_histolytica Entamoeba histolytica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OMI FirstGlance]. <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]] 1.77&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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'>[https://proteopedia.org/fgij/fg.htm?mol=8omi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8omi OCA], [https://pdbe.org/8omi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8omi RCSB], [https://www.ebi.ac.uk/pdbsum/8omi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8omi ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/N9UNA8_ENTH1 N9UNA8_ENTH1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development of potent IP6K inhibitors is gaining momentum, a pharmacological tool to distinguish the mammalian isozymes is still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed a high-throughput screen to identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency and selectivity toward the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type (WT) kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by hydrogen deuterium exchange mass spectrometry measurements. The latter analysis suggested that displacement of the alphaC helix, caused by the gatekeeper mutation, facilitates the binding of FMP-201300 to an allosteric pocket adjacent to the ATP-binding site. FMP-201300 therefore serves as a valuable springboard for the further development of compounds that can selectively target the three mammalian IP6Ks; either as analog-sensitive kinase inhibitors or as an allosteric lead compound for the WT kinases.

An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor.,Aguirre T, Dornan GL, Hostachy S, Neuenschwander M, Seyffarth C, Haucke V, Schutz A, von Kries JP, Fiedler D Elife. 2023 Oct 16;12:RP88982. doi: 10.7554/eLife.88982. PMID:37843983<ref>PMID:37843983</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8omi" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Entamoeba histolytica]]
[[Category: Large Structures]]
[[Category: Aguirre T]]
[[Category: Fiedler D]]
[[Category: Schuetz A]]