2NRY

Crystal structure of IRAK-4

Summary for 2NRY

• Entry DOI: 10.2210/pdb2nry/pdb
• Related: 2NRU
• Descriptor: interleukin-1 receptor-associated kinase 4, STAUROSPORINE (3 entities in total)
• Functional Keywords: kinase, inhibitor, staurosporine, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 139858.04

Authors

Wang, Z.,Liu, J.,Walker, N.P.C. (deposition date: 2006-11-02, release date: 2006-12-12, Last modification date: 2024-10-16)

Primary citation

Wang, Z.,Liu, J.,Sudom, A.,Ayres, M.,Li, S.,Wesche, H.,Powers, J.P.,Walker, N.P.C.
Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper.
Structure, 14:1835-1844, 2006

PubMed 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.

PubMed: 17161373
DOI: 10.1016/j.str.2006.11.001

Experimental method

X-RAY DIFFRACTION (2.15 Å)