6DL7

Human mitochondrial ClpP in complex with ONC201 (TIC10)

6DL7 の概要

• エントリーDOI: 10.2210/pdb6dl7/pdb
• 分子名称: 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)
• 機能のキーワード: protease, mitochondria, homeostasis, degradation, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 171950.44

構造登録者

Halgas, O.,Zarabi, S.F.,Schimmer, A.,Pai, E.F. (登録日: 2018-05-31, 公開日: 2019-05-08, 最終更新日: 2024-03-13)

主引用文献

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

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: 31056398
DOI: 10.1016/j.ccell.2019.03.014

実験手法

X-RAY DIFFRACTION (2 Å)