Structural characterization of activation ‘intermediate 2’ on the pathway to human gastricsin

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Abstract

The crystal structure of an activation intermediate of human gastricsin has been determined at 2.4 Å resolution. The human digestive enzyme gastricsin (pepsin C) is an aspartic proteinase that is synthesized as the inactive precursor (zymogen) progastricsin (pepsinogen C or 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. Zymogen conversion occurs in an autocatalytic and stepwise fashion at low pH through the formation of intermediates. The structure of the non-covalent complex of a partially-cleaved peptide of the prosegment (Ala 1p–Phe 26p) with mature gastricsin (Ser 1–Ala 329) suggests an activation pathway that may be common to all gastric aspartic proteinases.

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Khan, A., Cherney, M., Tarasova, N. et al. Structural characterization of activation ‘intermediate 2’ on the pathway to human gastricsin. Nat Struct Mol Biol 4, 1010–1015 (1997) doi:10.1038/nsb1297-1010

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