9z2f | pdb_00009z2f

Mitochondrial Creatine Kinase in complex with ADP and uncompetitive inhibitor uci

spinqualitylabelsall models 9z2f, resolution 2.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9z2f is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.59Å Ligands: A1CZQ, ADP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KCRU_HUMAN 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 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 bioRxiv [Preprint]. 2026 Jan 8:2026.01.08.696683. doi: , 10.64898/2026.01.08.696683. PMID:41542558 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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