6DL7
Human mitochondrial ClpP in complex with ONC201 (TIC10)
Summary for 6DL7
| Entry DOI | 10.2210/pdb6dl7/pdb |
| Descriptor | ATP-dependent Clp protease proteolytic subunit, mitochondrial, 7-benzyl-4-[(2-methylphenyl)methyl]-6,7,8,9-tetrahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one (3 entities in total) |
| Functional Keywords | protease, mitochondria, homeostasis, degradation, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 7 |
| Total formula weight | 171950.44 |
| Authors | Halgas, O.,Zarabi, S.F.,Schimmer, A.,Pai, E.F. (deposition date: 2018-05-31, release date: 2019-05-08, Last modification date: 2024-03-13) |
| Primary citation | Ishizawa, J.,Zarabi, S.F.,Davis, R.E.,Halgas, O.,Nii, T.,Jitkova, Y.,Zhao, R.,St-Germain, J.,Heese, L.E.,Egan, G.,Ruvolo, V.R.,Barghout, S.H.,Nishida, Y.,Hurren, R.,Ma, W.,Gronda, M.,Link, T.,Wong, K.,Mabanglo, M.,Kojima, K.,Borthakur, G.,MacLean, N.,Ma, M.C.J.,Leber, A.B.,Minden, M.D.,Houry, W.,Kantarjian, H.,Stogniew, M.,Raught, B.,Pai, E.F.,Schimmer, A.D.,Andreeff, M. Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell, 35:721-, 2019 Cited by PubMed Abstract: The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis. PubMed: 31056398DOI: 10.1016/j.ccell.2019.03.014 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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