title: X-ray crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1.
abstract: Interleukin (IL-1)alpha and IL-1beta are important mediators of inflammation. The binding of IL-1 to interleukin-1 receptor (IL-1R) type 1 is the initial step in IL-1 signal transduction and therefore is a tempting target for anti-inflammatory therapeutics. To advance our understanding of IL-1R1 binding interactions, we have determined the structure of the extracellular domains of IL-1R1 bound to a 21-amino acid IL-1 antagonist peptide at 3.0-A resolution. The antagonist peptide binds to the domain 1/2 junction of the receptor, which is a conserved binding site for IL-1beta and IL-1 receptor antagonist (IL-1ra). This co-crystal structure also reveals that considerable flexibility is present in IL-1R1 because the carboxyl-terminal domain of the receptor is rotated almost 170 degrees relative to the first two domains of the receptor compared with the previously solved IL-1R1.ligand structures. The structure shows an unexpected binding mode for the peptide and may contribute to the design of smaller IL-1R antagonists.
authors.affiliation: Department of Inflammation Research, Amgen, Incorporated, Boulder, Colorado 80301, USA. gvigers@arraybiopharma.com
authors.forename: G P
authors.initials: GP
authors.lastname: Vigers
authors.forename: D J
authors.initials: DJ
authors.lastname: Dripps
authors.forename: C K
authors.initials: CK
authors.lastname: Edwards
authors.forename: B J
authors.initials: BJ
authors.lastname: Brandhuber
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D053590:Interleukin 1 Receptor Antagonist Protein; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins / Q000737:chemistry* / Q000378:metabolism*; D018411:Spodoptera
chemical_list: C417509:AF 10847; D000596:Amino Acids; D053590:Interleukin 1 Receptor Antagonist Protein; D010455:Peptides; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins