View source for 6hx1


==IRE1 ALPHA IN COMPLEX WITH imidazo[1,2-b]pyridazin-8-amine compound 2==
<StructureSection load='6hx1' size='340' side='right'caption='[[6hx1]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hx1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HX1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HX1 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]] 2.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GXK:6-chloranyl-~{N}-(cyclopropylmethyl)-3-(2~{H}-indazol-5-yl)imidazo[1,2-b]pyridazin-8-amine'>GXK</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=6hx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hx1 OCA], [https://pdbe.org/6hx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hx1 RCSB], [https://www.ebi.ac.uk/pdbsum/6hx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hx1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ERN1_HUMAN ERN1_HUMAN] Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.<ref>PMID:9637683</ref> <ref>PMID:11175748</ref> <ref>PMID:12637535</ref> [UniProtKB:Q9EQY0]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors was discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1alpha (IRE1alpha), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1alpha oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1alpha kinase domain that would be incompatible with back-to-back dimerization of the IRE1alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1alpha kinase site that allosterically inhibit the endoribonuclease.

Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1alpha kinase-endoribonuclease.,Colombano G, Caldwell JJ, Matthews TP, Bhatia C, Joshi A, McHardy T, Mok NY, Newbatt Y, Pickard L, Strover J, Hedayat S, Walton MI, Myers S, Jones AM, Saville H, McAndrew C, Burke R, Eccles S, Davies F, Bayliss R, Collins I J Med Chem. 2019 Feb 19. doi: 10.1021/acs.jmedchem.8b01721. PMID:30779566<ref>PMID:30779566</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6hx1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ire1|Ire1]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Augustin MA]]
[[Category: Bayliss R]]
[[Category: Collins I]]
[[Category: Krapp S]]