PDBsum entry 6w3a

Transferase

PDB id: 6w3a

Contents

Protein chains

363 a.a.

371 a.a.

Ligands

SJM ×2

Waters ×42

References listed in PDB file

Key reference

• Title: Activation of the ire1 rnase through remodeling of the kinase front pocket by ATP-Competitive ligands.
• Authors: E.Ferri, A.Le thomas, H.A.Wallweber, E.S.Day, B.T.Walters, S.E.Kaufman, M.G.Braun, K.R.Clark, M.H.Beresini, K.Mortara, Y.A.Chen, B.Canter, W.Phung, P.S.Liu, A.Lammens, A.Ashkenazi, J.Rudolph, W.Wang.
• Ref.: Nat Commun, 2020, 11, 6387. [DOI no: 10.1038/s41592-019-0459-y]
• PubMed id: 33318494

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.