6c91: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of GRP94 with a resorcinylic inhibitor.== | ==Structure of GRP94 with a resorcinylic inhibitor.== | ||
<StructureSection load='6c91' size='340' side='right' caption='[[6c91]], [[Resolution|resolution]] 2.90Å' scene=''> | <StructureSection load='6c91' size='340' side='right'caption='[[6c91]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6c91]] 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=6C91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C91 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6c91]] 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=6C91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C91 FirstGlance]. <br> | ||
| Line 24: | Line 24: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Canlf]] | [[Category: Canlf]] | ||
[[Category: Large Structures]] | |||
[[Category: Gewirth, D T]] | [[Category: Gewirth, D T]] | ||
[[Category: Que, N L.S]] | [[Category: Que, N L.S]] | ||
Revision as of 12:57, 4 December 2019
Structure of GRP94 with a resorcinylic inhibitor.Structure of GRP94 with a resorcinylic 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 PubMedGrp94 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||