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| | <StructureSection load='6asp' size='340' side='right'caption='[[6asp]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='6asp' size='340' side='right'caption='[[6asp]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6asp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Canlf Canlf]. 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> | + | <table><tr><td colspan='2'>[[6asp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris]. 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 [https://proteopedia.org/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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.696Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90B1, GRP94, TRA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9615 CANLF])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6asp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6asp OCA], [https://pdbe.org/6asp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6asp RCSB], [https://www.ebi.ac.uk/pdbsum/6asp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6asp ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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). | + | [https://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). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6asp" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6asp" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Heat Shock Protein structures|Heat Shock Protein structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Canlf]] | + | [[Category: Canis lupus familiaris]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Huard, D J.E]] | + | [[Category: Huard DJE]] |
| - | [[Category: Lieberman, R L]] | + | [[Category: Lieberman RL]] |
| - | [[Category: Chaperone-inhibitor complex]]
| + | |
| - | [[Category: Glaucoma]]
| + | |
| - | [[Category: Grp94]]
| + | |
| - | [[Category: Hsp90]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| Structural highlights
Function
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).
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma. ACS Chem Biol. 2018 Feb 20. doi: 10.1021/acschembio.7b01083. PMID:29402077 doi:http://dx.doi.org/10.1021/acschembio.7b01083
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