6W3C

Structure of phosphorylated apo IRE1

Summary for 6W3C

• Entry DOI: 10.2210/pdb6w3c/pdb
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1 (2 entities in total)
• Functional Keywords: kinase, upr, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 199205.72

Authors

Wallweber, H.,Mortara, K.,Ferri, E.,Wang, W.,Rudolph, J. (deposition date: 2020-03-09, release date: 2020-12-09, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)