C3, C4 and C5: the thioester site.

with a hydrophobic cluster of Tyr-59, Ile-60 and Leu-63 on one surface. It is this hydrophobic cluster that we suggest is being mimicked by the tryptophanyl-tryptophan groups as illustrated in Fig. 1. We also propose that the hydrophobic cluster in C3a represents a secondary binding site on the molecule, and it is a cooperative interaction on the receptor between the hydrophobic and effector sites (LGLAR) that results in the full activity of C3a and the C3a fragment C3a 57-77. If this concept is accurate, then the secondary binding site, defined properly only when the C-terminal region of C3a is in a helix. can be reproduced in a linear array by selecting hydrophobic groups of the appropriate shape and size. This model explains why the length of the supraagonist peptides can be optimized since the distance between the acceptor sites on the receptor are relatively fixed. The importance of this model may be far reaching for complex protein molecules that depend on a folded conformation for activity. Instead of attempting to mimic the secondary o r tertiary conformational motif, it seems entirely possible to organize the essential features of the binding site in a linear array. Furthermore, in understanding the nature o r structural requirements of the binding sites in biological factors, one may actually improve on the interactions permitting designs of linear supra-agonists without need or benefit of the secondary or tertiary folding constraints.