9B0U
Cryo-EM structure of E227Q variant of uMtCK1 incubated with ADP and phosphocreatine at pH 8.0
Summary for 9B0U
| Entry DOI | 10.2210/pdb9b0u/pdb |
| EMDB information | 44058 |
| Descriptor | Creatine kinase U-type, mitochondrial, N-[(E)-AMINO(IMINO)METHYL]-N-METHYLGLYCINE, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | mitochondrial creatine kinase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 8 |
| Total formula weight | 386202.75 |
| Authors | Demir, M.,Koepping, L.,Zhao, J.,Sergienko, E. (deposition date: 2024-03-12, release date: 2025-02-12, Last modification date: 2025-04-16) |
| Primary citation | 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 Cited by 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: 39904336DOI: 10.1016/j.str.2025.01.008 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.44 Å) |
Structure validation
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