PDBsum entry 4pl5

Transferase,hydrolase/inhibitor

PDB id: 4pl5

Contents

Protein chains

383 a.a.

Ligands

ADP ×4

31L

PEU

Metals

_MG ×4

PDB id:

4pl5

Name:

Transferase,hydrolase/inhibitor

Title:

Crystal structure of murine ire1 in complex with oicr573 inhibitor

Structure:

Serine/threonine-protein kinase/endoribonuclease ire1. Chain: b, a, c, d. Fragment: unp residues 550-977. Synonym: endoplasmic reticulum-to-nucleus signaling 1,inositol- requiring protein 1,ire1-alpha,ire1a. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: ern1, ire1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.40Å R-factor: 0.225 R-free: 0.285

Authors:

M.Sanches,N.Duffy,M.Talukdar,N.Thevakumaran,D.Chiovitti,R.Al-Awar, J.B.Patterson,F.Sicheri

Key ref:

M.Sanches et al. (2014). Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun, 5, 4202. PubMed id: 25164867 DOI: 10.1038/ncomms5202

Date:

16-May-14 Release date: 03-Sep-14

Protein chains

Q9EQY0  (ERN1_MOUSE) -  Serine/threonine-protein kinase/endoribonuclease IRE1 from Mus musculus

Seq: 977 a.a.

Struc: 383 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = ADP) corresponds exactly) + 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: 10.1038/ncomms5202

Nat Commun 5:4202 (2014)

PubMed id: 25164867

Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.

M.Sanches, N.M.Duffy, M.Talukdar, N.Thevakumaran, D.Chiovitti, M.D.Canny, K.Lee, I.Kurinov, D.Uehling, R.Al-awar, G.Poda, M.Prakesch, B.Wilson, V.Tam, C.Schweitzer, A.Toro, J.L.Lucas, D.Vuga, L.Lehmann, D.Durocher, Q.Zeng, J.B.Patterson, F.Sicheri.

ABSTRACT

Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.