Selective inhibition of hsp90 paralogs: Structure and binding studies uncover the role of helix 1 in Grp94-selective ligand binding

Grp94 may be the endoplasmic reticulum paralog from the hsp90 group of chaperones, that have been focused on therapeutic intervention via their highly conserved ATP binding sites. The style of paralog-selective inhibitors depends on comprehending the structural factors that mediate each paralog’s reaction to inhibitor binding. Here, we determined the structures of Grp94 and Hsp90 in complex using the Grp94-selective inhibitor PU-H36, as well as Grp94 using the non-selective inhibitor PU-H71. In Grp94, the 8-aryl moiety of PU-H36 is placed into Site 2, a conditionally available side pocket, however in Hsp90 it occupies Site 1, a non-selective side pocket that’s available in all hsp90 paralogs.

The dwelling of Grp94 in complex using the non-selective PU-H71 shows only Site 1 binding. Large conformational shifts involving helices 1, 4 and 5 from the N-terminal domain of Grp94 are connected using the engagement from the Site 2 pocket for ligand binding. To know the origins of Site 2 pocket engagement, we tested the PU-H71 binding of Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These research has shown that helix one of the Grp94 N-terminal domain may be the discriminating element that enables for remodeling from the ATP binding pocket and exposure from the Site 2 selective pocket.