title: Structural definition of the C5a C terminus by two-dimensional nuclear magnetic resonance spectroscopy.
abstract: The serum glycoprotein C5a, which is derived from the proteolytic cleavage of complement protein C5, has been implicated in the pathogenesis of a number of inflammatory and allergic conditions. Because C5a induces an inflammatory response upon binding to a specific receptor, structural and mutagenesis studies were carried out to gain a better understanding of this binding interaction. These studies led to the first structural definition of the C terminus of recombinant human (rh)-C5a, determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy. Our results show that the C terminus adopts an alpha-helical conformation spanning residues 69 to 74, while the core domain exists as an antiparallel alpha-helical bundle. This C-terminal helix is connected to the core by a short loop that orients Arg 74 adjacent to Arg 62. Point mutation analysis had already revealed that residues 62 and 74 significantly contribute to agonist activity and receptor binding. Correlation of the C5a tertiary structure with mutational analyses clarifies the significance of the functional and binding properties of Arg 62 and suggests that both Arg 62 and Arg 74 interact at the same binding site on the receptor.
authors.affiliation: Novartis Pharmaceuticals Corp., Summit, New Jersey 07901, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Boyar
authors.forename: M J
authors.initials: MJ
authors.lastname: Toth
authors.forename: L
authors.initials: L
authors.lastname: Wennogle
authors.forename: N C
authors.initials: NC
authors.lastname: Gonnella
mesh_terms: D000595:Amino Acid Sequence; D015936:Complement C5a / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D011994:Recombinant Proteins; D015936:Complement C5a