8HGK

Crystal structure of human ClpP in complex with ZK53

Summary for 8HGK

• Entry DOI: 10.2210/pdb8hgk/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, 4-[[3,5-bis(fluoranyl)phenyl]methyl]-N-[(4-bromophenyl)methyl]piperazine-1-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: activator, zk53, human clpp, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 345939.33

Authors

Yang, C.-G.,Gan, J.H.,Zhou, L.-L. (deposition date: 2022-11-14, release date: 2023-09-27, Last modification date: 2024-04-17)

Primary citation

Zhou, L.L.,Zhang, T.,Xue, Y.,Yue, C.,Pan, Y.,Wang, P.,Yang, T.,Li, M.,Zhou, H.,Ding, K.,Gan, J.,Ji, H.,Yang, C.G.
Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma.
Nat Commun, 14:7069-7069, 2023

PubMed Abstract: Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. However, we are currently unaware of any studies using selective and potent ClpP activators in lung squamous cell carcinoma. In this work, we report on such an activator, ZK53, which exhibits therapeutic effects on lung squamous cell carcinoma in vivo. The crystal structure of ZK53/ClpP complex reveals a π-π stacking effect that is essential for ligand binding selectively to the mitochondrial ClpP. ZK53 features on a simple scaffold, which is distinct from the activators with rigid scaffolds, such as acyldepsipeptides and imipridones. ZK53 treatment causes a decrease of the electron transport chain in a ClpP-dependent manner, which results in declined oxidative phosphorylation and ATP production in lung tumor cells. Mechanistically, ZK53 inhibits the adenoviral early region 2 binding factor targets and activates the ataxia-telangiectasia mutated-mediated DNA damage response, eventually triggering cell cycle arrest. Lastly, ZK53 exhibits therapeutic effects on lung squamous cell carcinoma cells in xenograft and autochthonous mouse models.

PubMed: 37923710
DOI: 10.1038/s41467-023-42784-4

Experimental method

X-RAY DIFFRACTION (1.9 Å)