More recently, inhibitors of the C terminus of Hsp90 have been developed and studied in vitro with promising results. The Hsp90 molecular chaperone is a highly abundant eukaryotic molecular chaperone. Using a chemical-biology approach, we characterized the features driving the Hsp90 physical interactome. 1, 2 One or more cytosolic HSP90 isoform is found in all eukaryotes, and many higher eukaryotes also possess specialized mitochondrial (TRAP1) and endoplasmic reticulum (GRP94/GP96/endoplasmin). An essential eukaryotic component of the chaperone system is Hsp90. The HSP90s are a family of molecular chaperones that function in the cellular stabilization, regulation, and activation of a range of ‘client’ proteins. In addition, to the N-terminal site of Hsp90, the C-terminal site appears to be another target for inhibition of Hsp90. PMID: 37295430 DOI: 10.1016/j.molcel.2023.05.021 Abstract Molecular chaperones govern proteome health to support cell homeostasis. Subsequent analogues-17 allylamino-17demethoxygeldanamycin and 17 dimethylaminoethylamino-17-demethoxygeldanamycin-were found to be more clinically appropriate and have been studied in a number of clinical trials since 1999. The N-terminal inhibitors, geldanamycin and radiciol, were the first two described inhibitors of Hsp90, but were not clinically useful. As Hsp90 has been found to be either overexpressed or constitutively more active in cancer cells, inhibitors of Hsp90 may have cancer cell selectivity. Disruption of Hsp90 leads to client protein degradation and often cell death. Hsp90 molecular chaperones in eukaryotic cells play essential roles in the folding and activation of a range of client proteins involved in cell cycle. Under stressful conditions, Hsp90 stabilizes its client proteins and provides protection to the cell against cellular stressors such as in cancer cells. Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the trafficking of proteins in the cell.
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