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4pl3

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Revision as of 07:18, 4 August 2016

Crystal structure of murine IRE1 in complex with MKC9989 inhibitor

Structural highlights

4pl3 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4pl4, 4pl5
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002 Feb 15;16(4):452-66. PMID:11850408 doi:http://dx.doi.org/10.1101/gad.964702
↑ 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. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202. PMID:25164867 doi:http://dx.doi.org/10.1038/ncomms5202

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4pl3"

@@ Line 1: / Line 1: @@
 ==Crystal structure of murine IRE1 in complex with MKC9989 inhibitor==
 <StructureSection load='4pl3' size='340' side='right' caption='[[4pl3]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=31J:7-HYDROXY-6-METHOXY-3-[2-(2-METHOXYETHOXY)ETHYL]-4,8-DIMETHYL-2H-CHROMEN-2-ONE'>31J</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</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">[[4pl4|4pl4]], [[4pl5|4pl5]]</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=4pl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pl3 PDBsum]</span></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=4pl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl3 OCA], [http://pdbe.org/4pl3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pl3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pl3 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4pl3" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4pl3

From Proteopedia

Revision as of 07:18, 4 August 2016

Crystal structure of murine IRE1 in complex with MKC9989 inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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