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Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.
Highlights
The Hsp[90] molecular chaperone has been the target of many clinical and pre-clinical drug discovery programmes in the pharmaceutical industry and academic laboratories[1,2,3]
In the present work we rigorously investigate the druggability of Hsp90-organising protein (Hop) TPR2A and provide clear evidence confirming the challenging nature of this target
Our new structure shows that the Hop TPR2A domain is, in solution, fully folded in the absence of its Hsp[90] binding partner and is highly similar to the X-ray crystal structure of Hop TPR2A co-crystallised with the Hsp[90] C-terminus (Supplementary Fig. S2)[21]
Summary
The Hsp[90] molecular chaperone has been the target of many clinical and pre-clinical drug discovery programmes in the pharmaceutical industry and academic laboratories[1,2,3]. Thought to contribute to the therapeutic effectiveness of Hsp[90] inhibitors is that they block a second, broader role of Hsp[90] in maintaining cellular proteostasis This role is important under conditions of high levels of protein production in cancer cells and potentially in the hypoxic tumour microenvironment[1]. These varied interactions allow Hop to stabilise open, client-ready conformations of Hsp[90] and slow ATP hydrolysis[19] In addition to this well studied molecular role in client transfer, Hop has been linked to a variety of other biological effects including HSF1 transcriptional activity, tumour cell invasion and endothelial cell polarisation and migration[26,27,28], perhaps suggesting particular downstream biological roles for this cochaperone
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