title: Structure of a CXC chemokine-receptor fragment in complex with interleukin-8.
abstract: BACKGROUND
  Interactions between CXC chemokines (e.g. interleukin-8, IL-8) and their receptors (e.g. CXCR-1) have a key role in host defense and disease by attracting and upregulating neutrophils to sites of inflammation. The transmembrane nature of the receptor impedes structure-based understanding of ligand interactions. Linear peptides based on the N-terminal, extracellular portion of the receptor CXCR-1 do bind to IL-8, however, and inhibit the binding of IL-8 to the full-length receptor.
  
  
  RESULTS
  The NMR solution structure of the complex formed between IL-8 and one such receptor-based peptide indicates that a cleft between a loop and a beta hairpin constitute part of the receptor interaction surface on IL-8. Nine residues from the C terminus of the receptor peptide (corresponding to Pro21-Pro29 of CXCR-1) occupy the cleft in an extended fashion. Intermolecular contacts are mostly hydrophobic and sidechain mediated.
  
  
  CONCLUSIONS
  The results offer the first details at an atomic level of the interaction between a chemokine and its receptor. Consideration of other biochemical data allow extrapolation to a model for the interaction of IL-8 with the full-length receptor. In this model, the heparin-binding residues of IL-8 are exposed, thereby allowing presentation of the chemokine from endothelial cell-surface glycosaminoglycans. This first glimpse of how IL-8 binds to its receptor provides a foundation for the structure-based design of chemokine antagonists.
authors.affiliation: Department of Protein Engineering Genentech, Inc. South San Francisco, CA 94080, USA. skelly@gene.com
authors.forename: N J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: C
authors.initials: C
authors.lastname: Quan
authors.forename: D
authors.initials: D
authors.lastname: Reilly
authors.forename: H
authors.initials: H
authors.lastname: Lowman
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry*; D006025:Glycosaminoglycans / Q000378:metabolism; D016209:Interleukin-8 / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000737:chemistry*; D023062:Receptors, Interleukin-8A
chemical_list: D015703:Antigens, CD; D006025:Glycosaminoglycans; D016209:Interleukin-8; D008565:Membrane Proteins; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A