UNIQUE BINDING OF A NOVEL SYNTHETIC INHIBITOR, BONYL]PHENYL]-2-METHYL-2-PROPENOY1]-N-ALLYLGLYCINE METHANESULFONATE, TO BOVINE TRYPSIN, REVEALED BY THE CRYSTAL-STRUCTURE OF THE COMPLEX

Trypsin and bonyl]phenyl]-2-methyl-2-propenoyl]-N-allylglycine methane sulfonate (1), a newly designed and orally active synthetic trypsin in hibitor, were cocrystallized. The space group of the crystal is P2(1)2 (1)2(1) with cell constants a = 63.74 Angstrom, b = 63.08 Angstrom, an d c = 69.38 Angstrom, which is nearly identical to that of the orthorh ombic crystal of guanidinobenzoyltrypsin. The structure was refined to a crystallographic residual R = 0.176. The refined model of the 1-try psin complex provides the structural basis for the reaction mechanism of 1. On the basis of the present X-ray results, it is proposed that t he potent inhibitory activity of 1 is mainly due to the formation of a n acylated trypsin through an ''inverse substrate mechanism'' and its low rate of deacylation.