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6W39

Structure of unphosphorylated IRE1 in complex with G-1749

Summary for 6W39
Entry DOI10.2210/pdb6w39/pdb
DescriptorSerine/threonine-protein kinase/endoribonuclease IRE1, ethyl ~{N}-[6-methyl-5-[3-[2-[[(3~{S})-piperidin-3-yl]amino]pyrimidin-4-yl]pyridin-2-yl]oxy-naphthalen-1-yl]carbamate (3 entities in total)
Functional Keywordskinase, upr, transferase
Biological sourceHomo sapiens (Human)
Total number of polymer chains2
Total formula weight99603.68
Authors
Ferri, E.,Wang, W.,Joachim, R.,Mortara, K. (deposition date: 2020-03-09, release date: 2020-12-09, Last modification date: 2023-10-18)
Primary citationFerri, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.736 Å)
Structure validation

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