Solution structure of a unique C5a semi-synthetic antagonist: implications in receptor binding.
The tertiary structure of a unique C5a receptor antagonist was determined by two-dimensional NMR spectroscopy. The core domain of this 8-kDa antagonist exists as an antiparallel helical bundle, similar to recombinant human (rh)-C5a. However, unlike C5a, the antagonist's C terminus was found to be conformationally restricted along a groove between helices one and four in the core domain. This conformational restriction situates C-terminal D-Arg 75 in a wedge between core residues Arg 46 and His 15. Correlation of the antagonist's tertiary structure with point mutation analysis revealed the formation of a positively charged contiguous contact surface comprised of D-Arg 75, Arg 46, Lys 49, and His 15. The significance of this surface in generating antagonist properties implies a single binding site with the C5a receptor and provides a structural template for drug design.
Zhang
X
X
Ciba-Geigy Corporation, Pharmaceuticals Division, Summit, New Jersey 07901, USA.
Boyar
W
W
Galakatos
N
N
Gonnella
N C
NC
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; D015936:Complement C5a