PDBsum entry 6ege

Transferase/transferase inhibitor

PDB id: 6ege

Contents

Protein chains

284 a.a.

270 a.a.

Ligands

DL1 ×2

Waters ×672

PDB id:

6ege

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of the unphosphorylated irak4 kinase domain bound to a type i inhibitor

Structure:

Interleukin-1 receptor-associated kinase 4. Chain: d, a. Fragment: protein kinase domain residues 164-460. Synonym: irak-4,renal carcinoma antigen ny-ren-64. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: irak4. Expressed in: trichoplusia ni. Expression_system_taxid: 7111

Resolution:

1.40Å R-factor: 0.179 R-free: 0.201

Authors:

R.Ferrao,Q.Liu,H.Wu

Key ref:

L.Wang et al. (2019). Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4). J Biol Chem, 294, 4511-4519. PubMed id: 30679311 DOI: 10.1074/jbc.RA118.005428

Date:

19-Aug-18 Release date: 13-Feb-19

Protein chain

Q9NWZ3  (IRAK4_HUMAN) -  Interleukin-1 receptor-associated kinase 4 from Homo sapiens

Seq: 460 a.a.

Struc: 284 a.a.*

Protein chain

Q9NWZ3  (IRAK4_HUMAN) -  Interleukin-1 receptor-associated kinase 4 from Homo sapiens

Seq: 460 a.a.

Struc: 270 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains D, A: 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⁺

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

reference

DOI no: 10.1074/jbc.RA118.005428

J Biol Chem 294:4511-4519 (2019)

PubMed id: 30679311

Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).

L.Wang, R.Ferrao, Q.Li, J.M.Hatcher, H.G.Choi, S.J.Buhrlage, N.S.Gray, H.Wu.

ABSTRACT

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key player in innate immune and inflammatory responses, performing a critical role in signal transduction downstream of Toll-like receptors and interleukin-1 (IL-1) receptors. Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation. To date, all known IRAK4 structures are in the active conformation, precluding a good understanding of IRAK4's conformational dynamics. To address this issue, here we first solved three crystal structures of the IRAK4 kinase domain (at ≤2.6 Å resolution), in its unphosphorylated, inactive state bound to either the ATP analog AMP-PNP or to one of the two small-molecule inhibitors JH-I-25 and JH-I-17. The structures disclosed that although the structure in complex with AMP-PNP is in an "αC-out" inactive conformation, those in complex with type I inhibitors assume an active "Asp-Phe-Gly (DFG)-in" and "αC-in" conformation. The ability of unphosphorylated IRAK4 to take on variable conformations prompted us to screen for small-molecule inhibitors that bind preferentially to unphosphorylated IRAK4, leading to the identification of ponatinib and HG-12-6. Solving the structures of unphosphorylated IRAK4 in complex with these two inhibitors, we found that they both bind as type II inhibitors with IRAK4 in a "DFG-out" conformation. Collectively, these structures reveal conformational flexibility of unphosphorylated IRAK4 and provide unexpected insights into the potential use of small molecules to modulate IRAK4 activity in cancer, autoimmunity, and inflammation.