Abstract:Allosteric inhibition of Hsp90 via a mechanism used by the NSC145366-based probes is a promising avenue for selective oncogenic client downregulation.
“…3-red). The observed orientation of the binding Site-1 ligands together with their corresponding interacting residues is in close agreement with a previous biochemical and in silico study of Bisphenol A based allosteric inhibitors of human Hsp90 42 . Furthermore, interacting residues L672, S674, and P681 are closely positioned to, and overlap with, several CTD allosteric hotspots (residues599-W606, and T669-L678) which have previously been implicated in NTD allosteric signalling and control of conformational dynamics 33 .Figure 3Time evolution of residue contribution to protein-ligand hydrophobic and hydrogen bond interactions.…”
Section: Resultssupporting
confidence: 90%
“…Subsequent to this discovery, further studies have led to the development of several allosteric CTD ligands that appear to enhance ATPase activity up to six-fold by promoting conformational dynamics in favour of the ATPase active closed conformation 39,40 . Furthermore, a recent biochemical study has provided evidence of Bisphenol A based CTD inhibitors of human Hsp90α that bind a site separate from the nucleotide binding site 41 and display anti-proliferative activity in tumour cell lines 42 . In a previous computational study, we used all-atom molecular dynamics (MD) simulations coupled with dynamic residue networks (DRN) and perturbation response scanning (PRS) to determine allosteric hotspots that may be implicated in modulating conformational dynamics in human Hsp90α 37 .…”
Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90α for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3β-isoferulate and 3′-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90’s conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90’s complex allosteric mechanism of action.
“…3-red). The observed orientation of the binding Site-1 ligands together with their corresponding interacting residues is in close agreement with a previous biochemical and in silico study of Bisphenol A based allosteric inhibitors of human Hsp90 42 . Furthermore, interacting residues L672, S674, and P681 are closely positioned to, and overlap with, several CTD allosteric hotspots (residues599-W606, and T669-L678) which have previously been implicated in NTD allosteric signalling and control of conformational dynamics 33 .Figure 3Time evolution of residue contribution to protein-ligand hydrophobic and hydrogen bond interactions.…”
Section: Resultssupporting
confidence: 90%
“…Subsequent to this discovery, further studies have led to the development of several allosteric CTD ligands that appear to enhance ATPase activity up to six-fold by promoting conformational dynamics in favour of the ATPase active closed conformation 39,40 . Furthermore, a recent biochemical study has provided evidence of Bisphenol A based CTD inhibitors of human Hsp90α that bind a site separate from the nucleotide binding site 41 and display anti-proliferative activity in tumour cell lines 42 . In a previous computational study, we used all-atom molecular dynamics (MD) simulations coupled with dynamic residue networks (DRN) and perturbation response scanning (PRS) to determine allosteric hotspots that may be implicated in modulating conformational dynamics in human Hsp90α 37 .…”
Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90α for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3β-isoferulate and 3′-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90’s conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90’s complex allosteric mechanism of action.
“…Using molecular dynamics simulations and a variety of mutant Hsp90 constructs, we were able to confirm the binding of LA1011 into a pocket formed by a variety of loops from the C-terminal and middle-domains of Hsp90. The mobility of such loops could provide a flexible platform for the binding of a variety of similar compounds that have been shown to bind the C-terminal domain of Hsp90 (Marcu et al, 2000 ; Donnelly and Blagg, 2008 ; Lee et al, 2011 ; Kusuma et al, 2012 ; Sattin et al, 2015 ; Vettoretti et al, 2016 ; Goode et al, 2017 ), but also the flexibility to provide binding in both the open and closed states of Hsp90. It is also noteworthy that the C-terminal domain of Hsp90 has been implicated as a client protein binding site (Genest et al, 2013 ) and client protein is known to activate the ATPase activity of Hsp90 (McLaughlin et al, 2002 ).…”
Section: Discussionmentioning
confidence: 99%
“…Unlike N-terminal inhibitors, the benzofuran derivatives did not induce the HSR, but reduced the levels of Hsp90 dependent client proteins such as ErbB2, Akt, Cdk4, and Survivin (Sattin et al, 2015 ). In contrast to activators, a set of structurally-symmetrical chemical derivatives based on NSC145366, which contains a bisphenol A core, were shown to be allosteric inhibitors of the ATPase activity of Hsp90 (Goode et al, 2017 ). These derivatives compromised the chaperoning function of Hsp90, by inhibiting its ability to prevent the aggregation of citrate synthase and the refolding of luciferase.…”
Chaperones play a pivotal role in protein homeostasis, but with age their ability to clear aggregated and damaged protein from cells declines. Tau pathology is a driver of a variety of neurodegenerative disease and in Alzheimer's disease (AD) it appears to be precipitated by the formation of amyloid-β (Aβ) aggregates. Aβ-peptide appears to trigger Tau hyperphosphorylation, formation of neurofibrillary tangles and neurotoxicity. Recently, dihydropyridine derivatives were shown to upregulate the heat shock response (HSR) and provide a neuroprotective effect in an APPxPS1 AD mouse model. The HSR response was only seen in diseased cells and consequently these compounds were defined as co-inducers since they upregulate chaperones and co-chaperones only when a pathological state is present. We show for compounds tested herein, that they target predominantly the C-terminal domain of Hsp90, but show some requirement for its middle-domain, and that binding stimulates the chaperones ATPase activity. We identify the site for LA1011 binding and confirm its identification by mutagenesis. We conclude, that binding compromises Hsp90's ability to chaperone, by modulating its ATPase activity, which consequently induces the HSR in diseased cells. Collectively, this represents the mechanism by which the normalization of neurofibrillary tangles, preservation of neurons, reduced tau pathology, reduced amyloid plaque, and increased dendritic spine density in the APPxPS1 Alzheimer's mouse model is initiated. Such dihydropyridine derivatives therefore represent potential pharmaceutical candidates for the therapy of neurodegenerative disease, such as AD.
“…Subsequent to this discovery, further studies have led to the development of several allosteric CTD ligands that appear to enhance ATPase activity up to six-fold by promoting conformational dynamics in favour of the ATPase active closed conformation 39,40 . Furthermore, a recent biochemical study has provided evidence of Bisphenol A based CTD inhibitors of human Hsp90α that bind a site separate from the nucleotide binding site 41 and display anti-proliferative activity in tumour cell lines 42 . In a previous computational study, we used all-atom molecular dynamics (MD) simulations coupled with dynamic residue networks (DRN) and perturbation response scanning (PRS) to determine allosteric hotspots that may be implicated in modulating conformational dynamics in human Hsp90α 37 .…”
Section: Figure 1: Illustration Of Hsp90α In the Open Conformation (A)mentioning
Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90α for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3β-isoferulate and 3'-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90's conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90's complex allosteric mechanism of action.
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