5TTZ

Crystal structure of Grp94 bound to isoform-selective inhibitor methyl 2-(2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)ethyl)-3-chloro-4,6-dihydroxybenzoate

Summary for 5TTZ

• Entry DOI: 10.2210/pdb5ttz/pdb
• Descriptor: Endoplasmin, methyl 2-(2-{1-[(4-bromophenyl)methyl]-1H-imidazol-2-yl}ethyl)-3-chloro-4,6-dihydroxybenzoate, DI(HYDROXYETHYL)ETHER, ... (7 entities in total)
• Functional Keywords: bnim scaffold, atp binding site, chaperone - inhibitor complex, chaperone / inhibitor
• Biological source: Canis lupus familiaris (Dog)
• Total number of polymer chains: 2
• Total formula weight: 54111.64

Authors

Lieberman, R.L.,Huard, D.J.E. (deposition date: 2016-11-04, release date: 2018-01-10, Last modification date: 2023-10-04)

Primary citation

Stothert, A.R.,Suntharalingam, A.,Tang, X.,Crowley, V.M.,Mishra, S.J.,Webster, J.M.,Nordhues, B.A.,Huard, D.J.E.,Passaglia, C.L.,Lieberman, R.L.,Blagg, B.S.J.,Blair, L.J.,Koren, J.,Dickey, C.A.
Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma.
Sci Rep, 7:17951-17951, 2017

PubMed Abstract: The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94-selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding.

PubMed: 29263415
DOI: 10.1038/s41598-017-18344-4

Experimental method

X-RAY DIFFRACTION (2.707 Å)