title: Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper.
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.
authors.affiliation: Department of Molecular Structure, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. zwang@amgen.com <zwang@amgen.com>
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
authors.forename: Merrill
authors.initials: M
authors.lastname: Ayres
authors.forename: Shyun
authors.initials: S
authors.lastname: Li
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D010710:Phosphates / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010710:Phosphates; D018698:Glutamic Acid; D014443:Tyrosine; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D053592:Interleukin-1 Receptor-Associated Kinases