EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Uncompetitive Allosteric Inhibitor of Mitochondrial Creatine Kinase Prevents Binding and Release of Creatine by Stabilization of Loop Closure.
ジャーナル・号・ページ	bioRxiv, Year 2026
掲載日	2026年1月8日
PubMed 要旨	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 ...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 , including fast-equilibrium and time-dependent orthosteric and allosteric inhibitors. Select hits were subjected to 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.
リンク	bioRxiv / PubMed:41542558 / PubMed Central
手法	EM (単粒子)
解像度	2.59 - 2.6 Å
構造データ	73766 9z2d EMDB-73766, PDB-9z2d: Mitochondrial Creatine Kinase in complex with ADP, creatine, and uncompetitive inhibitor uci 手法: EM (単粒子) / 解像度: 2.6 Å 73767 9z2f EMDB-73767, PDB-9z2f: Mitochondrial Creatine Kinase in complex with ADP and uncompetitive inhibitor uci 手法: EM (単粒子) / 解像度: 2.59 Å
化合物	ChemComp-ADP: ADENOSINE-5'-DIPHOSPHATE / ADP, エネルギー貯蔵分子YM ChemComp-CRN: N-[(E)-AMINO(IMINO)METHYL]-N-METHYLGLYCINE PDB-1czq: CRYSTAL STRUCTURE OF THE D10-P1/IQN17 COMPLEX: A D-PEPTIDE INHIBITOR OF HIV-1 ENTRY BOUND TO THE GP41 COILED-COIL POCKET. ChemComp-MG*: Unknown entry
由来	homo sapiens (ヒト)
キーワード	TRANSFERASE/INHIBITOR / Kinase / inhibitor / TRANSFERASE-INHIBITOR complex / transition state analog