7VP9

Crystal structure of human ClpP in complex with ZG111

Summary for 7VP9

• Entry DOI: 10.2210/pdb7vp9/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, (6S,9aS)-N-[(4-bromophenyl)methyl]-6-[(2S)-butan-2-yl]-8-(naphthalen-1-ylmethyl)-4,7-bis(oxidanylidene)-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: mitochondrial protease, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 347084.21

Authors

Wang, P.Y.,Gan, J.H.,Yang, C.-G. (deposition date: 2021-10-15, release date: 2022-06-08, Last modification date: 2023-11-29)

Primary citation

Wang, P.,Zhang, T.,Wang, X.,Xiao, H.,Li, H.,Zhou, L.L.,Yang, T.,Wei, B.,Zhu, Z.,Zhou, L.,Yang, S.,Lu, X.,Zhang, Y.,Huang, Y.,Gan, J.,Yang, C.G.
Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.
Cell Chem Biol, 29:1396-1408.e8, 2022

PubMed Abstract: The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.

PubMed: 35905743
DOI: 10.1016/j.chembiol.2022.07.002

Experimental method

X-RAY DIFFRACTION (2.552 Å)