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

Nature Structural Biology volume 4, pages 1010–1015 (1997)Cite this article

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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Authors and Affiliations

  1. MRC Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    Amir R. Khan, Maia M. Cherney & Michael N. G. James

  2. Molecular Aspects of Drug Design Section, ABL-Basic Research Program, National Cancer Institute, FCRDC, P.O. Box B, Frederick, Maryland, 21702, USA

    Nadezhda I. Tarasova

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  4. Michael N. G. James
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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). https://doi.org/10.1038/nsb1297-1010

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