A noncanonical mechanism of carboxypeptidase inhibition revealed by the crystal structure of the tri-Kunitz SmCI in complex with human CPA4

Maday Alonso Del Rivero, Mey L. Reytor, Sebastian A. Trejo, María A. Chávez, Francesc X. Avilés, David Reverter

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

The crystal structure of SmCI (Sabellastarte magnifica carboxypeptidase inhibitor) has been determined in complex with human carboxypeptidase A4 (hCPA4). SmCI is composed by three BPTI/Kunitz domains, each one displaying high structural homology and functionality with serine protease inhibitors. Moreover, SmCI possesses a distinctive capability to inhibit metallo-carboxypeptidases, constituting a bifunctional metallocarboxy- and serine protease inhibitor. The structure of the 1:1 complex of SmCI with hCPA4 reveals a noncanonical mechanism of carboxypeptidase inhibition, which surprisingly occurs mainly via the N-terminal segment, which penetrates into the active site groove of the enzyme. Mutagenesis and biochemical analysis confirm the major role of the N-terminal segment in the inhibition of carboxypeptidases. SmCI represents a tri-Kunitz serine protease inhibitor adapted to inhibit metallo-carboxypeptidases and discloses an unusual mechanism of inhibition by the N-terminal segment, emulating the "classical" C-terminal substrate-like inhibition. © 2013 Elsevier Ltd.
Original languageEnglish
Pages (from-to)1118-1126
JournalStructure
Volume21
Issue number7
DOIs
Publication statusPublished - 2 Jul 2013

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