Hsp90

The molecular chaperone Hsp90 is 1-2% of total soluble cell protein is one of the most abundant proteins in the cell. It is ubiquitous in eubacteria and all classes of eukaryotes. In archaea, however, it seems to be missing. During occurring cytoplasmic Hsp90 is essential for viability under all conditions, in eukaryotes, the bacterial homologue of HtpG is not essential under non- stress conditions. In mammalian cells, encoded by two genes, cytosolic Hsp90 homologs. The first indication that there is a heat shock protein Hsp90 in, came from studies with monkey cells and the fruit fly Drosophila melanogaster, which showed an increased Hsp90 expression under non-physiological conditions.

Structural properties of Hsp90

Hsp90 consists of three domains: a highly conserved amino-terminal ATPase domain, a middle domain and a carboxy-terminal dimerization domain.

The Hsp90 ATPase activity

The ATP hydrolysis seems crucial for the function of Hsp90 in vivo to be, since mutants that can not hydrolyze ATP, the vital functions of Hsp90 can not run. The crystal structure of the amino terminal domain of Hsp90 in complex with ATP showed that - in contrast to most other ATP -hydrolyzing proteins - ATP is bound in an abnormally folded conformation.

Inhibitors - Hsp90 as a drug target

Geldanamycin and herbimycin A are so related ansamycins from fungi which have antitumor activity. Geldanamycin binds to the amino-terminal domain of Hsp90 as a competitive inhibitor of ATP. The affinity of geldanamycin to Hsp90 is approximately 500 - fold higher than that of ATP. Radicicol ( mono or gestures ) is a macrolactone from a fungus and binds with nanomolar affinity to Hsp90. Crystal studies have shown that radicicol binds to the amino-terminal ATP - binding pocket of Hsp90. The fact that completely different classes can bind natural substances with high specificity and affinity to the ATP - binding pocket of Hsp90 and the identification of a number of anti-tumor proteins as Hsp90 substrates have led to the idea that one could use Hsp90 as a drug target. First clinical studies with human compatible Geldanamycinderivaten, such as 17 -AAG (17 - allylamino -17 - demethoxygeldanamycin ), showing at nanomolar concentrations potent antitumor activity against a variety of cancers, are already conducted in many countries.

Function of Hsp90

The molecular chaperone Hsp70 and Hsp90 are responsible for folding and activation of many substrate proteins. Among the most important representatives of Hsp70 and Hsp90 -dependent proteins include p53 steroid hormone receptors, transcription factors, kinases and the tumor suppressor protein. Hsp70 and Hsp90 Multichaperonkomplex form in which both of a third protein ( hop ) are connected. The interaction and the interaction of these two Chaperonmaschinen is of high importance for the survival of cells and organisms.