The three-dimensional structure of human procarboxypeptidase A2. Deciphering the basis of the inhibition, activation and intrinsic activity of the zymogen

Isabel García-Sáez, David Reverter, Josep Vendrell, Francesc X. Avilés, Miquel Coll

Research output: Contribution to journalArticleResearchpeer-review

90 Citations (Scopus)

Abstract

The three-dimensional structure of human procarboxypeptidase A2 has been determined using X-ray crystallography at 1.8 Å resolution. This is the first detailed structural report of a human pancreatic carboxypeptidase and of its zymogen. Human procarboxypeptidase A2 is formed by a pro-segment of 96 residues, which inhibits the enzyme, and a carboxypeptidase moiety of 305 residues. The pro-enzyme maintains the general fold when compared with other non-human counterparts. The globular part of the pro-segment docks into the enzyme moiety and shields the S2-S4 substrate binding sites, promoting inhibition. Interestingly, important differences are found in the pro-segment which allow the identification of the structural determinants of the diverse activation behaviours of procarboxypeptidases A1, B and A2, particularly of the latter. The benzylsuccinic inhibitor is able to diffuse into the active site of procarboxypeptidase A2 in the crystals. The structure of the zymogen-inhibitor complex has been solved at 2.2 Å resolution. The inhibitor enters the active site through a channel formed at the interface between the pro-segment and the enzyme regions and interacts with important elements of the active site. The derived structural features explain the intrinsic activity of A1/A2 pro-enzymes for small substrates.
Original languageEnglish
Pages (from-to)6906-6913
JournalEMBO Journal
Volume16
Issue number23
DOIs
Publication statusPublished - 1 Dec 1997

Keywords

  • Activation
  • Carboxypeptidase A2
  • Inhibition
  • Pro-enzyme
  • Three-dimensional structure

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