Engineering functional antithrombin exosites in alpha1-proteinase inhibitor that specifically promote the inhibition of factor Xa and factor IXa.

ABSTRACT: We have previously shown that residues Tyr-253 and Glu-255 in the serpin antithrombin function as exosites to promote the inhibition of factor Xa and factor IXa when the serpin is conformationally activated by heparin. Here we show that functional exosites can be engineered at homologous positions in a P1 Arg variant of the serpin alpha1-proteinase inhibitor (alpha1PI) that does not require heparin for activation. The combined effect of the two exosites increased the association rate constant for the reactions of alpha1PI with factors Xa and IXa 11-14-fold, comparable with their rate-enhancing effects on the reactions of heparin-activated antithrombin with these proteases. The effects of the engineered exosites were specific, alpha1PI inhibitor reactions with trypsin and thrombin being una

SUBMITTER: Izaguirre G 

PROVIDER: S-EPMC2615528 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature