4PL5

Crystal structure of murine IRE1 in complex with OICR573 inhibitor

4PL5 の概要

• エントリーDOI: 10.2210/pdb4pl5/pdb
• 関連するPDBエントリー: 4PL3 4PL4
• 分子名称: Serine/threonine-protein kinase/endoribonuclease IRE1, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: schiff base, hydroxy aryl aldehydes (haa), inhibitor complex, unfolded protein response, endoribonuclease, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 204652.38

構造登録者

Sanches, M.,Duffy, N.,Talukdar, M.,Thevakumaran, N.,Chiovitti, D.,Al-awar, R.,Patterson, J.B.,Sicheri, F. (登録日: 2014-05-16, 公開日: 2014-09-03, 最終更新日: 2024-11-13)

主引用文献

Sanches, M.,Duffy, N.M.,Talukdar, M.,Thevakumaran, N.,Chiovitti, D.,Canny, M.D.,Lee, K.,Kurinov, I.,Uehling, D.,Al-Awar, R.,Poda, G.,Prakesch, M.,Wilson, B.,Tam, V.,Schweitzer, C.,Toro, A.,Lucas, J.L.,Vuga, D.,Lehmann, L.,Durocher, D.,Zeng, Q.,Patterson, J.B.,Sicheri, F.
Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.
Nat Commun, 5:4202-4202, 2014

PubMed Abstract: Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α 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 IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α 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 IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

PubMed: 25164867
DOI: 10.1038/ncomms5202

実験手法

X-RAY DIFFRACTION (3.4 Å)