PDBsum entry 4z7h

Transferase

PDB id: 4z7h

Contents

Protein chains

385 a.a.

Ligands

4L5 ×2

SO4

Waters ×21

PDB id:

4z7h

Name:

Transferase

Title:

Crystal structure of human ire1 cytoplasmic kinase-rnase region - complex with imidazopyridine compound 3

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

Resolution:

2.90Å R-factor: 0.202 R-free: 0.225

Authors:

A.Joshi,R.Bayliss

Key ref:

A.Joshi et al. (2015). Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. Oncotarget, 6, 13019-13035. PubMed id: 25968568 DOI: 10.18632/oncotarget.3864

Date:

07-Apr-15 Release date: 27-May-15

Protein chains

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

Seq: 977 a.a.

Struc: 385 a.a.

Enzyme reactions

• Enzyme class 1: 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: 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: 10.18632/oncotarget.3864

Oncotarget 6:13019-13035 (2015)

PubMed id: 25968568

Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.

A.Joshi, Y.Newbatt, P.C.McAndrew, M.Stubbs, R.Burke, M.W.Richards, C.Bhatia, J.J.Caldwell, T.McHardy, I.Collins, R.Bayliss.

ABSTRACT

IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged. Structure-function analysis reveals that IRE1 is autoinhibited through a Tyr-down mechanism related to that found in the unrelated Ser/Thr protein kinase Nek7. We have developed a compound that potently inhibits human IRE1 kinase activity while stimulating XBP1 splicing. A crystal structure of the inhibitor bound to IRE1 shows an increased ordering of the kinase activation loop. The structures of hIRE in apo and ligand-bound forms are consistent with a previously proposed model of IRE1 regulation in which formation of a back-to-back dimer coupled to adoption of a kinase-active conformation drive RNase activation. The structures provide opportunities for structure-guided design of IRE1 inhibitors.