Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding
Year: 2018
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Structure and Regulation of hsp90 Chaperones, New paradigms for Hsp90 inhibition, The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors, Grp94-selective inhibitors to treat heredity glaucoma, G5099715671, The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors, Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy, G9000065363
OpenAlex ID: W2790774674