5wmt: Difference between revisions
From Proteopedia
Jump to navigationJump to search
m Protected "5wmt" [edit=sysop:move=sysop] |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of GRP94 N-terminal Domain bound to resorcinylic inhibitor BnIm.== | |||
<StructureSection load='5wmt' size='340' side='right' caption='[[5wmt]], [[Resolution|resolution]] 2.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5wmt]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WMT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WMT FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9QY:methyl+2-[2-(1-benzyl-1H-imidazol-2-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate'>9QY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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">[[5vyy|5vyy]]</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=5wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wmt OCA], [http://pdbe.org/5wmt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wmt RCSB], [http://www.ebi.ac.uk/pdbsum/5wmt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wmt 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). | |||
<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 5wmt" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Gewirth, D T]] | |||
[[Category: Que, N S]] | |||
[[Category: Chaperone]] | |||
[[Category: Chaperone-inhibitor complex]] | |||
[[Category: Complex]] | |||
[[Category: Inhibitor]] | |||
