Solution structure of a conformationally constrained Arg-Gly-Asp-like mothinserted into the alpha/beta scaffold of leiurotoxin I

A monoclonal antibody, AC7, directed against the RGD-binding site of the GP IIIa subunit of the platelet fibrinogen receptor, interacts with activated platelet. The H3 region (H3, RQMIRGYFDV sequence) of the complementarity-de termining region 3 heavy chain of AC7 inhibits platelet aggregation and fib rinogen binding to platelet. H3 contains the arginine, glycine and aspartat e residues, but in an unusual order. The solution structure of the decapept ide has been studied by proton NMR. The NMR data suggested a helical equili brium To test whether the helical structure of H3 was biologically relevant , a conformationally constrained peptide with the RGD-like motif was design ed. The sequence of a scorpion toxin (leiurotoxin I) has been modified in o rder to constrain the H3 sequence in a rigid helical conformation. The stru cture of leiurotoxin I consists of a beta-sheet and an alpha-helix, linked by three disulfide bridges. The structural feature of the chimeric peptide (H3-leiurotoxin) has been determined by standard two-dimensional NMR techni ques. H3-Leiurotoxin structure closely resembles that of leiurotoxin I.