A Noncanonical Mechanism of Carboxypeptidase Inhibition Revealed by the Crystal Structure of the Tri-Kunitz SmCI in Complex with Human CPA4

作者：Alonso del Rivero Maday; Reytor Mey L; Trejo Sebastian A; Chavez Maria A; Aviles Francesc X^*; Reverter David

来源：Structure, 2013, 21(7): 1118-1126.

DOI：10.1016/j.str.2013.04.021

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 %26quot;classical%26quot; C-terminal substrate-like inhibition.

• 出版日期2013-7-2