6BBA

Crystal structure of human mitochondrial ClpP complex with acyldepsipeptide ADEP-28

6BBA の概要

• エントリーDOI: 10.2210/pdb6bba/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, mitochondrial, Acyldepsipeptide ADEP-28 (3 entities in total)
• 機能のキーワード: protease, proteostasis, protein quality control, mitochondria, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 174893.57

構造登録者

Mabanglo, M.F.,Houry, W.A. (登録日: 2017-10-17, 公開日: 2018-07-11, 最終更新日: 2023-11-15)

主引用文献

Wong, K.S.,Mabanglo, M.F.,Seraphim, T.V.,Mollica, A.,Mao, Y.Q.,Rizzolo, K.,Leung, E.,Moutaoufik, M.T.,Hoell, L.,Phanse, S.,Goodreid, J.,Barbosa, L.R.S.,Ramos, C.H.I.,Babu, M.,Mennella, V.,Batey, R.A.,Schimmer, A.D.,Houry, W.A.
Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death.
Cell Chem Biol, 25:1017-1030.e9, 2018

PubMed Abstract: Acyldepsipeptides (ADEPs) are potential antibiotics that dysregulate the activity of the highly conserved tetradecameric bacterial ClpP protease, leading to bacterial cell death. Here, we identified ADEP analogs that are potent dysregulators of the human mitochondrial ClpP (HsClpP). These ADEPs interact tightly with HsClpP, causing the protease to non-specifically degrade model substrates. Dysregulation of HsClpP activity by ADEP was found to induce cytotoxic effects via activation of the intrinsic, caspase-dependent apoptosis. ADEP-HsClpP co-crystal structure was solved for one of the analogs revealing a highly complementary binding interface formed by two HsClpP neighboring subunits but, unexpectedly, with HsClpP in the compact conformation. Given that HsClpP is highly expressed in multiple cancers and has important roles in cell metastasis, our findings suggest a therapeutic potential for ADEPs in cancer treatment.

PubMed: 30126533
DOI: 10.1016/j.chembiol.2018.05.014

実験手法

X-RAY DIFFRACTION (2.796 Å)