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homolog to mature, human gastricsin, human pepsin 3 (18) allow one to construct a reasonably detailed view of the pathway followed in the conversion of the inactive zymogen to the active protease. Fig. 1 shows stereo ribbon diagrams of each of these three molecular structures. Fig. 2 shows a diagrammatic view of the conversion pathway. This pathway is a general pathway for the gastric aspartic proteases but the individual enzymes differ in detail.

FIG. 1. Structures on the conversion pathway of the aspartic protease zymogen progastricsin. The structure of human gastricsin is not known; the human pepsin structure therefore has been used as a model for gastricsin. This figure, as well as Figs. 3–6 have been prepared with BOBSCRIPT (19) and RASTER 3D (20). (A) The structure of human progastricsin (16) represented in stereo. The residues of the prosegment (Ala-1p to Leu-43p) are in green, those of the gastricsin portion of the zymogen are in blue except for those regions that undergo large conformational changes, Ser-1 to Ala-13, Phe-71 to Thr-81 and Tyr-125 to Ala-136, which are represented in mauve. The promature junction is Leu-43p-Ser-1, the peptide bond cleaved intramolecularly is Phe-26p to Leu-27p. The side chains of Asp-32 and Asp-217 are represented in red. (B) Stereo view of the molecular structure of intermediate 2 on the activation pathway of human gastricsin (17). The color scheme used is the same as in A. The residues missing on this figure, Leu-22p to Phe-26p and Ser-1, are disordered in the structure, and there is no interpret able electron density for them on the maps. The water molecule bound between the two carboxyl groups of Asp-32 and Asp-217 is shown as a red sphere. The final step in the conversion involves the dissociation of the peptide Ala-1p to Phe-26p from gastricsin with the N-terminal residues of gastricsin, Ser-1 (N-ter) to Ala-13, replacing the N-terminal ß-strand of the prosegment. (C) The structure of human pepsin (18) shown as a model of human gastricsin. The regions of gastricsin that undergo large conformational changes from their positions in progastricsin are shown in pink, and the active site aspartates with the bound catalytic H2O molecule are colored red. Reproduced with permission from ref. 3.

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