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Background: Canonical inhibitors interact with cognate proteases through a protease-binding loop.Results: Protease-binding loop of corn Hageman factor inhibitor (CHFI) does not inhibit its cognate enzyme-activated coagulation factor XII (FXIIa).Conclusion: Nonloop regions of CHFI are required for specific inhibition of FXIIa.Significance: CHFI is the first canonical inhibitor whose protease-binding loop is not sufficient for cognate enzyme inhibition.

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