8gm5
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Functional construct of the Eukaryotic elongation factor 2 kinase bound to Calmodulin, ADP and to the A-484954 inhibitor and showing two conformations for the 498-520 loop== | |
| + | <StructureSection load='8gm5' size='340' side='right'caption='[[8gm5]], [[Resolution|resolution]] 2.12Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8gm5]] is a 2 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=8GM5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GM5 FirstGlance]. <br> | ||
| + | </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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EKI:7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carboxamide'>EKI</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=8gm5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gm5 OCA], [https://pdbe.org/8gm5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gm5 RCSB], [https://www.ebi.ac.uk/pdbsum/8gm5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gm5 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/EF2K_HUMAN EF2K_HUMAN] Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.<ref>PMID:14709557</ref> <ref>PMID:9144159</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The calmodulin-activated alpha-kinase, eukaryotic elongation factor 2 kinase (eEF-2K) serves as a master regulator of translational elongation by specifically phosphorylating and reducing the ribosome-affinity of the guanosine triphosphatase, eukaryotic elongation factor 2 (eEF-2). Given its critical role in a fundamental cellular process, dysregulation of eEF-2K has been implicated in several human diseases, including those of the cardiovascular system, chronic neuropathies, and many cancers, making it a critical pharmacological target. In the absence of high-resolution structural information, high-throughput screening efforts have yielded small-molecule candidates that show promise as eEF-2K antagonists. Principal among these is the ATP-competitive pyrimido-pyrimidinedione inhibitor, A-484954, which shows high specificity towards eEF-2K relative to a panel of "typical" protein kinases. A-484954 has been shown to have some degree of efficacy in animal models of several disease states. It has also been widely deployed as a reagent in eEF-2K-specific biochemical and cell-biological studies. However, given the absence of structural information, the precise mechanism of the A-484954-mediated inhibition of eEF-2K has remained obscure. Leveraging our identification of the calmodulin-activatable catalytic core of eEF-2K and our recent determination of its long-elusive structure, here we present the structural basis for its specific inhibition by A-484954. This structure, which represents the first for an inhibitor-bound catalytic domain of a member of the alpha-kinase family, enables rationalization of the existing structure-activity relationship data for A-484954 variants and lays the groundwork for further optimization of this scaffold to attain enhanced specificity/potency against eEF-2K. | ||
| - | + | Structure of the complex between calmodulin and a functional construct of eukaryotic elongation factor 2 kinase bound to an ATP-competitive inhibitor.,Piserchio A, Isiorho EA, Dalby KN, Ghose R J Biol Chem. 2023 May 10:104813. doi: 10.1016/j.jbc.2023.104813. PMID:37172726<ref>PMID:37172726</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8gm5" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Dalby KN]] | ||
| + | [[Category: Ghose R]] | ||
| + | [[Category: Isiorho EA]] | ||
| + | [[Category: Piserchio A]] | ||
Revision as of 05:44, 31 May 2023
Functional construct of the Eukaryotic elongation factor 2 kinase bound to Calmodulin, ADP and to the A-484954 inhibitor and showing two conformations for the 498-520 loop
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