7uvr
Crystal structure of human ClpP protease in complex with TR-65
Structural highlights
FunctionCLPP_HUMAN Clp cleaves peptides in various proteins in a process that requires ATP hydrolysis. Clp may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates. Publication Abstract from PubMedThe 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. Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.,Mabanglo MF, Wong KS, Barghash MM, Leung E, Chuang SHW, Ardalan A, Majaesic EM, Wong CJ, Zhang S, Lang H, Karanewsky DS, Iwanowicz AA, Graves LM, Iwanowicz EJ, Gingras AC, Houry WA Structure. 2022 Dec 15:S0969-2126(22)00488-9. doi: 10.1016/j.str.2022.12.002. PMID:36586405[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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