View source for 6asp


==Structure of Grp94 with methyl 3-chloro-2-(2-(1-(2-ethoxybenzyl)-1 H-imidazol-2-yl)ethyl)-4,6-dihydroxybenzoate, a Grp94-selective inhibitor and promising therapeutic lead for treating myocilin-associated glaucoma==
<StructureSection load='6asp' size='340' side='right' caption='[[6asp]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6asp]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ASP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ASP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</scene>, <scene name='pdbligand=V2C:methyl+3-chloro-2-(2-(1-(2-ethoxybenzyl)-1+H-imidazol-2-yl)ethyl)-4,6-dihydroxybenzoate'>V2C</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6asp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6asp OCA], [http://pdbe.org/6asp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6asp RCSB], [http://www.ebi.ac.uk/pdbsum/6asp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6asp ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ENPL_CANLF ENPL_CANLF]] Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity (By similarity). 
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== Publication Abstract from PubMed ==
Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway. Here, we expanded our support for targeting Grp94 over cytosolic paralogs Hsp90alpha and Hsp90beta. We then developed a high-throughput screening assay to identify new chemical matter capable of disrupting the Grp94/OLF interaction. When applied to a blind, focused library of 17 Hsp90 inhibitors, our miniaturized single-read in vitro thioflavin T -based kinetics aggregation assay exclusively identified compounds that target the chaperone N-terminal nucleotide binding site. In follow up studies, one compound (2) decreased the extent of co-aggregation of Grp94 with OLF in a dose-dependent manner in vitro, and enabled clearance of the aggregation-prone full-length myocilin variant I477N in cells without inducing the heat shock response or causing cytotoxicity. Comparison of the co-crystal structure of compound 2 and another non-selective hit in complex with the N-terminal domain of Grp94 reveals a docking mode tailored to Grp94 and explains its selectivity. A new lead compound has been identified, supporting a targeted chemical biology assay approach to develop a protein degradation-based therapy for myocilin-associated glaucoma by selectively inhibiting Grp94.

Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma.,Huard DJE, Crowley VM, Du Y, Cordova RA, Sun Z, Tomlin MO, Dickey CA, Koren J 3rd, Blair L, Fu H, Blagg BSJ, Lieberman RL ACS Chem Biol. 2018 Feb 20. doi: 10.1021/acschembio.7b01083. PMID:29402077<ref>PMID:29402077</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Huard, D J.E]]
[[Category: Lieberman, R L]]
[[Category: Chaperone-inhibitor complex]]
[[Category: Glaucoma]]
[[Category: Grp94]]
[[Category: Hsp90]]
[[Category: Inhibitor]]