7UVM

Crystal structure of human ClpP protease in complex with TR-27

7UVM の概要

• エントリーDOI: 10.2210/pdb7uvm/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, mitochondrial, (10R)-4-[(4-chlorophenyl)methyl]-7-[(3-ethynylphenyl)methyl]-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one (3 entities in total)
• 機能のキーワード: agonist, protease, degradation, apoptosis, hydrolase, hydrolase-agonist complex, hydrolase/agonist
• 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: 172275.63

構造登録者

Mabanglo, M.F.,Houry, W.A. (登録日: 2022-05-02, 公開日: 2023-01-11, 最終更新日: 2023-10-25)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.19 Å)