Two-site binding of C5a by its receptor: an alternative binding paradigm for G protein-coupled receptors.
The guanine nucleotide-binding protein-coupled receptor superfamily binds a vast array of biological messengers including lipids, odorants, catecholamines, peptides, and proteins. While some small molecules bind to these receptors at a single interhelical site, we find that the binding domain on the receptor for the inflammatory protein C5a is more complex and consists of two distinct subsites. This more elaborate motif appears to be an evolutionary adaptation of the simpler paradigm to which a second interaction site has been added in the receptor N terminus. Surprisingly, occupation of only one of the subsites is required for receptor activation. The two-site motif is not unique to the C5a receptor but appears to be widely used by the superfamily to accommodate macromolecular ligands.
Siciliano
S J
SJ
Department of Immunology Research, Merck Research Laboratories, Rahway, NJ 07065.
Rollins
T E
TE
DeMartino
J
J
Konteatis
Z
Z
Malkowitz
L
L
Van Riper
G
G
Bondy
S
S
Rosen
H
H
Springer
M S
MS
D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008566:Membranes / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009504:Neutrophils / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D017421:Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection
D010446:Peptide Fragments; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a; D019204:GTP-Binding Proteins