6W3K

Structure of unphosphorylated human IRE1 bound to G-9807

6W3K の概要

• エントリーDOI: 10.2210/pdb6w3k/pdb
• 分子名称: Serine/threonine-protein kinase/endoribonuclease IRE1, 4-[5-[2,6-bis(fluoranyl)phenyl]-2~{H}-pyrazolo[3,4-b]pyridin-3-yl]-2-(4-oxidanylpiperidin-1-yl)-1~{H}-pyrimidin-6-one (3 entities in total)
• 機能のキーワード: kinase, inhibitor, allosteric activator, upr, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49985.90

構造登録者

Lammens, A.,Wang, W.,Ferri, E.,Rudolph, J. (登録日: 2020-03-09, 公開日: 2020-12-09, 最終更新日: 2023-10-18)

主引用文献

Ferri, E.,Le Thomas, A.,Wallweber, H.A.,Day, E.S.,Walters, B.T.,Kaufman, S.E.,Braun, M.G.,Clark, K.R.,Beresini, M.H.,Mortara, K.,Chen, Y.A.,Canter, B.,Phung, W.,Liu, P.S.,Lammens, A.,Ashkenazi, A.,Rudolph, J.,Wang, W.
Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.
Nat Commun, 11:6387-6387, 2020

PubMed Abstract: Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.

PubMed: 33318494
DOI: 10.1038/s41467-020-19974-5

実験手法

X-RAY DIFFRACTION (2.08 Å)