2yi6: Difference between revisions
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[[ | ==Structural characterization of 5-Aryl-4-(5-substituted-2-4- dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors.== | ||
<StructureSection load='2yi6' size='340' side='right' caption='[[2yi6]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2yi6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YI6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6QM:4-[5-(4-ETHOXYPHENYL)-1,2,3-THIADIAZOL-4-YL]-6-ETHYLBENZENE-1,3-DIOL'>6QM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yi0|2yi0]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[2ye4|2ye4]], [[2ye5|2ye5]], [[2bz5|2bz5]], [[2yei|2yei]], [[2ccs|2ccs]], [[2yeg|2yeg]], [[1yc3|1yc3]], [[1uyf|1uyf]], [[1uyi|1uyi]], [[2ye3|2ye3]], [[2byi|2byi]], [[2vci|2vci]], [[2wi1|2wi1]], [[2xjx|2xjx]], [[2xdk|2xdk]], [[2fwz|2fwz]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2xab|2xab]], [[2yeh|2yeh]], [[2xht|2xht]], [[1uy7|1uy7]], [[2xhr|2xhr]], [[2yef|2yef]], [[2byh|2byh]], [[2wi5|2wi5]], [[1yes|1yes]], [[1uy9|1uy9]], [[2cdd|2cdd]], [[1byq|1byq]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2ye7|2ye7]], [[2yeb|2yeb]], [[2uwd|2uwd]], [[2xhx|2xhx]], [[2wi7|2wi7]], [[2yej|2yej]], [[2bt0|2bt0]], [[1yer|1yer]], [[2yec|2yec]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2xk2|2xk2]], [[2xjj|2xjj]], [[1uyd|1uyd]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[2yee|2yee]], [[1uy6|1uy6]], [[2ye2|2ye2]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2ye9|2ye9]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[2cct|2cct]], [[2wi6|2wi6]], [[1yc1|1yc1]], [[2yea|2yea]], [[2ye6|2ye6]], [[2yed|2yed]], [[1uyc|1uyc]], [[1yet|1yet]], [[2jjc|2jjc]], [[2ye8|2ye8]], [[2yi7|2yi7]], [[2yi5|2yi5]]</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=2yi6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yi6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yi6 RCSB], [http://www.ebi.ac.uk/pdbsum/2yi6 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90alpha N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp90. | |||
Co-crystalization and in vitro biological characterization of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole hsp90 inhibitors.,Sharp SY, Roe SM, Kazlauskas E, Cikotiene I, Workman P, Matulis D, Prodromou C PLoS One. 2012;7(9):e44642. Epub 2012 Sep 11. PMID:22984537<ref>PMID:22984537</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
== | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Pearl, L H.]] | [[Category: Pearl, L H.]] | ||
Revision as of 14:57, 29 October 2014
Structural characterization of 5-Aryl-4-(5-substituted-2-4- dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors.Structural characterization of 5-Aryl-4-(5-substituted-2-4- dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors.
Structural highlights
Publication Abstract from PubMedA potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90alpha N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp90. Co-crystalization and in vitro biological characterization of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole hsp90 inhibitors.,Sharp SY, Roe SM, Kazlauskas E, Cikotiene I, Workman P, Matulis D, Prodromou C PLoS One. 2012;7(9):e44642. Epub 2012 Sep 11. PMID:22984537[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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