7UVR

Crystal structure of human ClpP protease in complex with TR-65

Summary for 7UVR

• Entry DOI: 10.2210/pdb7uvr/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, 3-{[(10R)-4-[(4-chlorophenyl)methyl]-5-oxo-1,2,4,5,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-7(6H)-yl]methyl}benzonitrile (3 entities in total)
• Functional Keywords: agonist, protease, degradation, apoptosis, cancer, hydrolase, hydrolase-agonist complex, hydrolase/agonist
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 7
• Total formula weight: 172282.54

Authors

Mabanglo, M.F.,Houry, W.A. (deposition date: 2022-05-02, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

Mabanglo, M.F.,Wong, K.S.,Barghash, M.M.,Leung, E.,Chuang, S.H.W.,Ardalan, A.,Majaesic, E.M.,Wong, C.J.,Zhang, S.,Lang, H.,Karanewsky, D.S.,Iwanowicz, A.A.,Graves, L.M.,Iwanowicz, E.J.,Gingras, A.C.,Houry, W.A.
Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.
Structure, 31:185-, 2023

PubMed Abstract: The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate reactive oxygen species (ROS)-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small-molecule agonists is a recent strategy in cancer therapy. Here, we synthesized imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular basis by which dysregulated ClpP affects cancer cell viability and proliferation.

PubMed: 36586405
DOI: 10.1016/j.str.2022.12.002

Experimental method

X-RAY DIFFRACTION (2.86 Å)