4pl4: Difference between revisions
New page: '''Unreleased structure''' The entry 4pl4 is ON HOLD Authors: Sanches, M., Duffy, N., Talukdar, M., Thevakumaran, N., Chiovitti, D., Al-awar, R., Patterson, J.B., Sicheri, F. Descripti... |
No edit summary |
||
| (9 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal structure of murine IRE1 in complex with OICR464 inhibitor== | ||
<StructureSection load='4pl4' size='340' side='right'caption='[[4pl4]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4pl4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PL4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PL4 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]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=31K:2-METHOXY-6-METHYL-4-(4-METHYL-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-7-YL)PHENOL'>31K</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEU:2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80-HEPTACOSAOXADOOCTACONTAN-82-OL'>PEU</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=4pl4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl4 OCA], [https://pdbe.org/4pl4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pl4 RCSB], [https://www.ebi.ac.uk/pdbsum/4pl4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pl4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ERN1_MOUSE ERN1_MOUSE] 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:11850408</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1alpha is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1alpha RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1alpha in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1alpha using small molecule inhibitors and suggest new avenues for inhibitor design. | |||
Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.,Sanches M, Duffy NM, Talukdar M, Thevakumaran N, Chiovitti D, Canny MD, Lee K, Kurinov I, Uehling D, Al-Awar R, Poda G, Prakesch M, Wilson B, Tam V, Schweitzer C, Toro A, Lucas JL, Vuga D, Lehmann L, Durocher D, Zeng Q, Patterson JB, Sicheri F Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202. PMID:25164867<ref>PMID:25164867</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4pl4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Ire1|Ire1]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Al-awar R]] | |||
[[Category: Chiovitti D]] | |||
[[Category: Duffy N]] | |||
[[Category: Patterson JB]] | |||
[[Category: Sanches M]] | |||
[[Category: Sicheri F]] | |||
[[Category: Talukdar M]] | |||
[[Category: Thevakumaran N]] | |||