9hrc
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of MNK2 in complex with inhibitor NUCC-0201049== | |
| + | <StructureSection load='9hrc' size='340' side='right'caption='[[9hrc]], [[Resolution|resolution]] 3.16Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9hrc]] 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=9HRC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HRC 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]] 3.161Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IWO:1-[5-chloranyl-4-[(3~{R})-pyrrolidin-3-yl]oxy-pyrimidin-2-yl]benzimidazole'>A1IWO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9hrc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hrc OCA], [https://pdbe.org/9hrc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hrc RCSB], [https://www.ebi.ac.uk/pdbsum/9hrc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hrc ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/MKNK2_HUMAN MKNK2_HUMAN] Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.<ref>PMID:11154262</ref> <ref>PMID:11463832</ref> <ref>PMID:12897141</ref> <ref>PMID:16111636</ref> <ref>PMID:17965020</ref> <ref>PMID:18299328</ref> <ref>PMID:20823271</ref> <ref>PMID:20927323</ref> <ref>PMID:21149447</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization. | ||
| - | + | Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia.,Vagadia PP, Izquierdo-Ferrer J, Mazewski C, Blyth G, Beauchamp EM, Clutter MR, Stern CL, Mishra RK, Nahotko D, Small S, Eckerdt F, Platanias LC, Schiltz GE J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03158. PMID:40033556<ref>PMID:40033556</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9hrc" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Schiltz GE]] | ||
| + | [[Category: Vagadia PV]] | ||
Current revision
Structure of MNK2 in complex with inhibitor NUCC-0201049
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