Cryo-EM structures of apo human Factor XIa reveal catalytic-domain flexibility and exposure of the Factor IX-binding site

Factor XI (FXI), a vital coagulation protease in the intrinsic blood coagulation pathway, holds promise as an antithrombotic target. However, the transformation of FXI from its inactive zymogen state to the active FXIa has remained elusive. A recent study employing cryo-electron microscopy (cryo-EM) has shed light on this transformation process.

The research reveals that the activation of FXI triggers a comprehensive restructuring of the homodimer, extending beyond the activation loop to encompass a considerable reorientation of the catalytic domain (CD) in relation to the apple-domain (AD) platform. This CD exhibits significant conformational variability, with the researchers identifying three distinct conformers. These findings suggest that FXIa exists as a dynamic ensemble rather than a rigid structure.

The activation process disrupts the allosteric communication between the catalytic domains present in the zymogen, thereby facilitating this structural flexibility. This increased plasticity in the CD allows for the dynamic exposure of the A3 exosite, a critical site for the binding of Factor IX. Interestingly, a comparison with plasma kallikrein (PKa), another apple-domain-containing contact-system protease, indicates that such structural flexibility may be a shared characteristic among these types of proteases.

These findings provide a structural framework for understanding substrate recognition by FXIa and identify novel, non-catalytic sites for the development of specific inhibitors against FXIa.