View source for 9z0p


==Mitochondrial Creatine Kinase in complex with uncompetitive inhibitor uci==
<StructureSection load='9z0p' size='340' side='right'caption='[[9z0p]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9z0p]] is a 8 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=9Z0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Z0P FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.56&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CZQ:[4-(2-azanyl-6-methyl-pyrimidin-4-yl)piperazin-1-yl]-(3,5,7-trimethyl-1~{H}-indol-2-yl)methanone'>A1CZQ</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=9z0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9z0p OCA], [https://pdbe.org/9z0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9z0p RCSB], [https://www.ebi.ac.uk/pdbsum/9z0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9z0p ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KCRU_HUMAN KCRU_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mitochondrial creatine kinase (MtCK) is a key enzyme in energy buffering and homeostasis in cells. It catalyzes transfer of phosphoryl group from ATP to creatine. Overexpression of MtCK occurs in many cancer cells to meet elevated energy demands, which is associated with poor prognosis. This suggests that MtCK may be a promising target for cancer therapeutics. We sought to discover first-in-class selective inhibitors of MtCK with diverse mechanisms of action using high-throughput screening, biochemical characterization and cryo-EM studies. Through these studies, we identified diverse types of compounds that modulate activity of MtCK in vitro, including fast-equilibrium and time-dependent orthosteric and allosteric inhibitors. Select hits were subjected to in vitro enzymatic and binding assays to assess MtCK inhibition and binding. A subset of inhibitors was advanced into structural studies using cryo-EM resulting in the molecular structure of MtCK with and without bound substrates in complex with an allosteric uncompetitive inhibitor that we discovered. These studies identified compound's unique binding pocket on MtCK and established the molecular steps manifesting in the apparent uncompetitive mode of inhibition. We demonstrate that the compound stabilizes an active site loop in a closed conformation restricting access of the creatine substrate to and the release of phosphocreatine product from its binding pocket. These findings establish highly specific chemical tools suitable for validation of MtCK as a promising breast cancer target with high therapeutic potential and build a foundation for future structure-guided optimization of the hit compounds of MtCK we identified and de novo rational design of novel MtCK inhibitors.

Uncompetitive Allosteric Inhibitor of Mitochondrial Creatine Kinase Prevents Binding and Release of Creatine by Stabilization of Loop Closure.,Demir M, Ma CT, Puvvula N, Koepping L, Gosalia P, Pollari S, Alba S, Zong Z, Li Y, Fujimoto L, Bobkov A, Hitosugi T, Zhao J, Sergienko E J Mol Biol. 2026 Jun 9;438(19):169896. doi: 10.1016/j.jmb.2026.169896. PMID:42264130<ref>PMID:42264130</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9z0p" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Demir M]]
[[Category: Sergienko E]]
[[Category: Zhao J]]