9B04

Cryo-EM structure of human uMtCK1 in complex with ADP

9B04 の概要

• エントリーDOI: 10.2210/pdb9b04/pdb
• EMDBエントリー: 44028
• 分子名称: Creatine kinase U-type, mitochondrial, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: mitochondrial creatine kinase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 384401.80

構造登録者

Demir, M.,Koepping, L.,Zhao, J.,Sergienko, E. (登録日: 2024-03-11, 公開日: 2025-02-12, 最終更新日: 2025-04-16)

主引用文献

Demir, M.,Koepping, L.,Li, Y.,Fujimoto, L.,Bobkov, A.,Zhao, J.,Hitosugi, T.,Sergienko, E.
Structural basis for substrate binding, catalysis, and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor.
Structure, 33:786-797.e3, 2025

PubMed Abstract: Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the "energy shuttle" for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.

PubMed: 39904336
DOI: 10.1016/j.str.2025.01.008

実験手法

ELECTRON MICROSCOPY (2.52 Å)