View source for 8tf0


==Crystal structure of Grp94 N-terminal domain bound to the purine inhibitor PU-H36==
<StructureSection load='8tf0' size='340' side='right'caption='[[8tf0]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tf0]] is a 4 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=8TF0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TF0 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.79&#8491;</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZUY:9-(pent-4-yn-1-yl)-8-[(2,4,6-trimethylphenyl)sulfanyl]-9H-purin-6-amine'>ZUY</scene></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=8tf0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tf0 OCA], [https://pdbe.org/8tf0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tf0 RCSB], [https://www.ebi.ac.uk/pdbsum/8tf0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tf0 ProSAT]</span></td></tr>
</table>
== Function ==
[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).
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== Publication Abstract from PubMed ==
Grp94 is the endoplasmic reticulum paralog of the hsp90 family of chaperones, which have been targeted for therapeutic intervention via their highly conserved ATP binding sites. The design of paralog-selective inhibitors relies on understanding the protein structural elements that drive higher affinity in selective inhibitors. Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94-selective inhibitor PU-H36, and of Grp94 with the non-selective inhibitor PU-H71. In Grp94, PU-H36 derives its higher affinity by utilizing Site 2, a Grp94-specific side pocket adjoining the ATP binding cavity, but in Hsp90 PU-H36 occupies Site 1, a side pocket that is accessible in all paralogs with which it makes lower affinity interactions. The structure of Grp94 in complex with PU-H71 shows only Site 1 binding. While changes in the conformation of helices 4 and 5 in the N-terminal domain occur when ligands bind to Site 1 of both Hsp90 and Grp94, large conformational shifts that also involve helix 1 are associated with the engagement of the Site 2 pocket in Grp94 only. Site 2 in Hsp90 is blocked and its helix 1 conformation is insensitive to ligand binding. To understand the role of helix 1 in ligand selectivity, we tested the binding of PU-H36 and other Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 is the major determinant of selectivity for Site 2 targeted ligands and also influences the rate of ATPase activity in Hsp90 paralogs.

Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding.,Que NLS, Seidler PM, Aw WJ, Chiosis G, Gewirth DT Proteins. 2024 Oct 29. doi: 10.1002/prot.26756. PMID:39473058<ref>PMID:39473058</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8tf0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Canis lupus familiaris]]
[[Category: Large Structures]]
[[Category: Gewirth DT]]
[[Category: Que NLS]]