STRUCTURAL CHARACTERIZATION OF ACTIVATION INTERMEDIATE-2 ON THE PATHWAY TO HUMAN GASTRICSIN

The crystal structure of an activation intermediate of human gastricsi n has been determined at 2.4 Angstrom resolution. The human digestive enzyme gastricsin (pepsin C) is an aspartic proteinase that is synthes ized as the inactive precursor (zymogen) progastricsin (pepsinogen C o r hPGC), In the zymogen, a positively-charged N-terminal prosegment of 43 residues (Ala 1p-Leu 43p; the suffix 'p' refers to the prosegment) sterically prevents the approach of a substrate to the active site. Z ymogen conversion occurs in an autocatalytic and stepwise fashion at l ow pH through the formation of intermediates. The structure of the non -covalent complex of a partially-cleaved peptide of the prosegment (Al a 1p-Phe 26p) with mature gastricsin (Ser l-Ala 329) suggests an activ ation pathway that may be common to all gastric aspartic proteinases.