6ceo: Difference between revisions
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==Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.== | |||
<StructureSection load='6ceo' size='340' side='right' caption='[[6ceo]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ceo]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CEO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CEO FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D57:dimethyl+2-[2-(1-benzyl-1H-imidazol-2-yl)ethyl]-4,6-dihydroxybenzene-1,3-dicarboxylate'>D57</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=6ceo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ceo OCA], [http://pdbe.org/6ceo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ceo RCSB], [http://www.ebi.ac.uk/pdbsum/6ceo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ceo ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.,Que NLS, Crowley VM, Duerfeldt AS, Zhao J, Kent CN, Blagg BSJ, Gewirth DT J Med Chem. 2018 Apr 12;61(7):2793-2805. doi: 10.1021/acs.jmedchem.7b01608. Epub , 2018 Mar 20. PMID:29528635<ref>PMID:29528635</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ceo" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Gewirth, D T]] | |||
[[Category: Que, N L.S]] | |||
[[Category: Chaperone]] | |||
[[Category: Chaperone-inhibitor complex]] | |||
[[Category: Inhibitor]] | |||
