Allosteric Regulation Points Control the Conformational Dynamics of the Molecular Chaperone Hsp90

Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation

“…Since in silico modeling cannot explain the oligomerization process, further investigation is required to probe the mechanistic details. Hsp90 appears to have multiple allosteric regulation points that are part of its conformational cycle; these may be modulated by interactions with co-chaperones [82,83] and mutations appear to affect oligomerization [83]. Although Hsp90 is a homodimer, it also exists in other oligomeric forms that are important for its biological activity including the ability to interact with clients and/or co-chaperones [66,84,85].…”

Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain

“…To date, biochemical and computational studies have demonstrated allosteric coupling between the NTD and CTD [33][34][35][36][37] suggesting nucleotide driven conformational restructuring may be influenced by allosteric events at the CTD. More specifically, computational studies based on the closed conformation of yeast Hsp90 have identified a putative allosteric binding site located at the Mdomain:CTD inter-protomer interface that is implicated in allosteric modulation of conformational dynamics 33,35,38 .…”

Allosteric Modulation of Conformational Dynamics in Human Hsp90α: A Computational Study

“…Residues L396-L409, listed in the closed but not the open complexes, represent the M-domain catalytic loop where they are thought to form an important interdomain hinge between the NTD and M-domain (Morra et al, 2012;Rehn et al, 2016). In addition to the this, S399 (Soroka et al, 2012), R400 (Meyer et al, 2003), E401 (Panaretou et al, 2002), and Q404 (Meyer et al, 2003) have been implicated in modulating ATPase activity and signal propagation Blacklock et al, 2014a).…”

“…In addition to the this, S399 (Soroka et al, 2012), R400 (Meyer et al, 2003), E401 (Panaretou et al, 2002), and Q404 (Meyer et al, 2003) have been implicated in modulating ATPase activity and signal propagation Blacklock et al, 2014a). The aromatic cluster formed by F384 and F441 are listed by BC in both conformations, and are thought to be important as allosteric control points for nucleotide dependent conformational change, acting as a mechanical hinge between the M-and CTDs (Morra et al, 2012;Rehn et al, 2016). Reside E451 is also selected in both conformations and mutation studies have shown that E451A decreases inter-protomer interactions leading to decreased ATPase activity (Rehn et al, 2016), while E451K is thought to perturb the M-domain structure impacting gluticoid receptor binding (Street et al, 2014).…”

“…The aromatic cluster formed by F384 and F441 are listed by BC in both conformations, and are thought to be important as allosteric control points for nucleotide dependent conformational change, acting as a mechanical hinge between the M-and CTDs (Morra et al, 2012;Rehn et al, 2016). Reside E451 is also selected in both conformations and mutation studies have shown that E451A decreases inter-protomer interactions leading to decreased ATPase activity (Rehn et al, 2016), while E451K is thought to perturb the M-domain structure impacting gluticoid receptor binding (Street et al, 2014). Phosphorylation mimicking mutations to S505 is fatal for yeast viability (S485) and is thought to impart resistance to ATP induced conformational transition to the closed state, favoring the open state (Soroka et al, 2012).…”