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 antibodie s and the ligands that they mimic. Originally, the competition of anti bodies 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 d etermining region (CDR) can adopt the same bioactive structures observ ed in ligands. Structure-function studies of three anti-GPIIb-IIIa mur ine 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 ce ll-surface adhesion ligands. The relative location of the guanidinium and carboxylate groups in the RXD regions is identified as an importan t recognition feature, and the conformational space occupied by this r egion in the antibodies is only slightly larger than that in the most bioactive peptides. Additionally, we show that antibodies can unveil o ther potential bioactive sequences, which may impart specificity. Thus antibodies are an exquisite probe for identifying motifs of short adh esion stretches, thereby revealing amino acid sequences and restricted geometries that might be used as lead compounds in drug design.