Bioactive Arg-Gly-Asp conformations in anti-integrin GPIIb-IIIa antibodies.
Antibodies can mimic the biological function of physiological ligands, yet few examples indicate the structural similarity between antibodies and the ligands that they mimic. Originally, the competition of antibodies for ligand binding sites was conjectured to be through similar three-dimensional conformations, which represent the "internal image" of the given ligand. Here we show that residues in a complementary determining region (CDR) can adopt the same bioactive structures observed in ligands. Structure-function studies of three anti-GPIIb-IIIa murine monoclonal antibodies, PAC-1, LJ-CP3, and OP-G2, indicate that the RYD sequence in their H-CDR3 domain occupies the same conformational space as RGD in conformationally constrained, bioactive, GPIIb-IIIa cell-surface adhesion ligands. The relative location of the guanidinium and carboxylate groups in the RXD regions is identified as an important recognition feature, and the conformational space occupied by this region in the antibodies is only slightly larger than that in the most bioactive peptides. Additionally, we show that antibodies can unveil other potential bioactive sequences, which may impart specificity. Thus antibodies are an exquisite probe for identifying motifs of short adhesion stretches, thereby revealing amino acid sequences and restricted geometries that might be used as lead compounds in drug design.
Prammer
K V
KV
Wistar Institute of Anatomy and Biology, University of Pennsylvania School of Medicine, Philadelphia.
Boyer
J
J
Ugen
K
K
Shattil
S J
SJ
Kieber-Emmons
T
T
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001667:Binding, Competitive; D002448:Cell Adhesion / Q000187:drug effects; D007128:Immunoglobulin Fragments / Q000378:metabolism; D016023:Integrins / Q000276:immunology*; D008546:Melanoma, Experimental / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D015335:Molecular Probes; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017433:Protein Structure, Secondary; D016024:Receptors, Cytoadhesin / Q000276:immunology*; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D016023:Integrins; D015335:Molecular Probes; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016024:Receptors, Cytoadhesin; C047981:arginyl-glycyl-aspartic acid