Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.
Bibliographical noteFunding Information:
D.T.G. is funded by grants from the NIH (Grants R01-CA095130, P01-CA186866) and the Richard and Mae Stone Goode Foundation of Buffalo. B.S.J.B. is supported by NIH Grant EY024232, and V.M.C. is supported by Grant F99212467 from the NCI. X-ray diffraction data were collected at the Advanced Photon Source beamlines 23ID-B and 17-ID and the Stanford Synchrotron Radiation Lab beamline BL9-2.
© 2018 American Chemical Society.