spacer
spacer

PDBsum entry 2nry

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transferase PDB id
2nry
Jmol
Contents
Protein chains
287 a.a. *
Ligands
STU ×4
Waters ×402
* Residue conservation analysis
PDB id:
2nry
Name: Transferase
Title: Crystal structure of irak-4
Structure: Interleukin-1 receptor-associated kinase 4. Chain: a, b, c, d. Fragment: protein kinase. Synonym: irak-4, ny- ren-64 antigen. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469
Biol. unit: Monomer (from PQS)
Resolution:
2.15Å     R-factor:   0.212     R-free:   0.261
Authors: Z.Wang,J.Liu,N.P.C.Walker
Key ref:
Z.Wang et al. (2006). Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Structure, 14, 1835-1844. PubMed id: 17161373 DOI: 10.1016/j.str.2006.11.001
Date:
02-Nov-06     Release date:   12-Dec-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9NWZ3  (IRAK4_HUMAN) -  Interleukin-1 receptor-associated kinase 4
Seq:
Struc:
460 a.a.
287 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     3 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.str.2006.11.001 Structure 14:1835-1844 (2006)
PubMed id: 17161373  
 
 
Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper.
Z.Wang, J.Liu, A.Sudom, M.Ayres, S.Li, H.Wesche, J.P.Powers, N.P.Walker.
 
  ABSTRACT  
 
Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a serine/threonine kinase that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs). Here, we report the crystal structures of the phosphorylated human IRAK-4 kinase domain in complex with a potent inhibitor and with staurosporine to 2.0 and 2.2 A, respectively. The structures reveal that IRAK-4 has a unique tyrosine gatekeeper residue that interacts with the conserved glutamate from helix alphaC. Consequently, helix alphaC is "pulled in" to maintain the active orientation, and the usual pre-existing hydrophobic back pocket of the ATP-binding site is abolished. The peptide substrate-binding site is more open when compared with other protein kinases due to a marked movement of helix alphaG. The pattern of phosphate ligand interactions in the activation loop bears a close resemblance to that of a tyrosine kinase. Our results provide insights into IRAK-4 function and the design of selective inhibitors.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Ribbon Diagram of the IRAK-4 Kinase Domain in Complex with Inhibitor Compound 1
The N-terminal extension preceding the kinase domain is shown in magenta. The activation segment is colored in red, and two phosphorylated residues, pThr345 and pSer346, are highlighted. Helix αG and its flanking loops are colored in cyan, and the extra loop between helices αD and αE is colored in orange. The inhibitor binding in the ATP cleft is shown as a molecular surface representation and is color coded green for carbon, blue for nitrogen, and red for oxygen.
Figure 6.
Figure 6. The Gatekeeper Region and ATP-Binding Pocket of IRAK-4
(A) The Tyr262 gatekeeper interacts with conserved Glu233 from helix αC through a direct hydrogen bond (shown as a magenta, dotted line) in the complex structure of IRAK-4 with compound 1 (shown as green sticks).
(B) The gatekeeper region of IRAK-4 in the presence of staurosporine (shown as yellow sticks).
(C and D) Molecular surface representation of the ATP-binding pocket in the presence of compound 1 and staurosporine, respectively.
 
  The above figures are reprinted by permission from Cell Press: Structure (2006, 14, 1835-1844) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21204785 H.Smith, X.Y.Liu, L.Dai, E.T.Goh, A.T.Chan, J.Xi, C.C.Seh, I.A.Qureshi, J.Lescar, C.Ruedl, R.Gourlay, S.Morton, J.Hough, E.G.McIver, P.Cohen, and P.C.Cheung (2011).
The role of TBK1 and IKKϵ in the expression and activation of Pellino 1.
  Biochem J, 434, 537-548.  
  20886024 C.G.Horton, Z.J.Pan, and A.D.Farris (2010).
Targeting Toll-like receptors for treatment of SLE.
  Mediators Inflamm, 2010, 0.  
20981241 J.Zhu, and C.Mohan (2010).
Toll-like receptor signaling pathways--therapeutic opportunities.
  Mediators Inflamm, 2010, 781235.  
19492062 A.A.Santos, C.M.Carvalho, L.H.Florentino, H.J.Ramos, and E.P.Fontes (2009).
Conserved threonine residues within the A-loop of the receptor NIK differentially regulate the kinase function required for antiviral signaling.
  PLoS One, 4, e5781.  
19752193 U.Maitra, J.S.Parks, and L.Li (2009).
An innate immunity signaling process suppresses macrophage ABCA1 expression through IRAK-1-mediated downregulation of retinoic acid receptor alpha and NFATc2.
  Mol Cell Biol, 29, 5989-5997.  
18691762 D.Wang, S.Fasciano, and L.Li (2008).
The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT.
  Mol Immunol, 45, 3902-3908.  
18249132 L.Ringwood, and L.Li (2008).
The involvement of the interleukin-1 receptor-associated kinases (IRAKs) in cellular signaling networks controlling inflammation.
  Cytokine, 42, 1-7.  
18266302 M.Koziczak-Holbro, A.Glück, C.Tschopp, J.C.Mathison, and H.Gram (2008).
IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes.
  Eur J Immunol, 38, 788-796.  
17337443 M.Koziczak-Holbro, C.Joyce, A.Glück, B.Kinzel, M.Müller, C.Tschopp, J.C.Mathison, C.N.Davis, and H.Gram (2007).
IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression.
  J Biol Chem, 282, 13552-13560.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.