Abstract
BackgroundHsp90 is an essential molecular chaperone that is also a novel anti-cancer drug target. There is growing interest in developing new drugs that modulate Hsp90 activity.Methodology/Principal FindingsUsing a virtual screening approach, 4-hydroxytamoxifen, the active metabolite of the anti-estrogen drug tamoxifen, was identified as a putative Hsp90 ligand. Surprisingly, while all drugs targeting Hsp90 inhibit the chaperone ATPase activity, it was found experimentally that 4-hydroxytamoxifen and tamoxifen enhance rather than inhibit Hsp90 ATPase.Conclusions/SignificanceHence, tamoxifen and its metabolite are the first members of a new pharmacological class of Hsp90 activators.
Highlights
Hsp90 is a ubiquitous ATP-dependent dimeric molecular chaperone that plays a central role in cellular signalling pathways since it is essential for maintaining the activity of several signalling proteins including steroid hormone receptors and protein kinases
4-hydroxytamoxifen (4-OHT), the active metabolite of TAM, was docked to the crystal structure of over 4000 druggable pockets extracted from the protein data bank using a virtual screening approach [19]
The results do not formally exclude the possibility that 4-OHT might bind at a site in Hsp82 N-domain (Hsp82N) different from that of the ATP pocket, which would cause an allosteric inhibition for the binding of ATP in the nucleotide pocket
Summary
Hsp is a ubiquitous ATP-dependent dimeric molecular chaperone that plays a central role in cellular signalling pathways since it is essential for maintaining the activity of several signalling proteins including steroid hormone receptors and protein kinases. Hsp90s typically function as part of large complexes that include other chaperones and essential cofactors regulating Hsp function. It is thought that different cofactors target Hsp to different sets of substrates. The broad effect of Hsp on protein cellular homeostasis arises from the large number of client substrates that this chaperone acts upon. More than one hundred Hsp substrates have been identified including a large number of transcription factors and protein kinases such as glucocorticoid receptor, p53 mutant, vSrc, Hck, CFTR, and many others [4]. Hsp is an essential molecular chaperone that is a novel anti-cancer drug target. There is growing interest in developing new drugs that modulate Hsp activity
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