PDBsum entry 6w3a

Transferase

PDB id: 6w3a

Contents

Protein chains

363 a.a.

371 a.a.

Ligands

SJM ×2

Waters ×42

PDB id:

6w3a

Name:

Transferase

Title:

Structure of unphosphorylated ire1 in complex with g-7658

Structure:

Serine/threonine-protein kinase/endoribonuclease ire1. Chain: a, b. Synonym: endoplasmic reticulum-to-nucleus signaling 1,inositol- requiring protein 1,hire1p,ire1-alpha,ire1a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ern1, ire1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9

Resolution:

2.61Å R-factor: 0.249 R-free: 0.290

Authors:

E.Ferri,W.Wang,R.Joachim,K.Mortara

Key ref:

E.Ferri et al. (2020). Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands. Nat Commun, 11, 6387. PubMed id: 33318494 DOI: 10.1038/s41592-019-0459-y

Date:

09-Mar-20 Release date: 09-Dec-20

Protein chain

O75460  (ERN1_HUMAN) -  Serine/threonine-protein kinase/endoribonuclease IRE1 from Homo sapiens

Seq: 977 a.a.

Struc: 363 a.a.

Protein chain

O75460  (ERN1_HUMAN) -  Serine/threonine-protein kinase/endoribonuclease IRE1 from Homo sapiens

Seq: 977 a.a.

Struc: 371 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: Chains A, B: E.C.3.1.26.- - ?????

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/s41592-019-0459-y

Nat Commun 11:6387 (2020)

PubMed id: 33318494

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.

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.

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.