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

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Abstract Factor XI (FXI) is a key coagulation protease of the intrinsic pathway of blood coagulation and an emerging antithrombotic target. However, the structural transition from zymogen to active Factor XIa (FXIa) has remained poorly understood. Using cryo-EM, we demonstrate that FXI activation results in a global reorganization of the homodimer, extending beyond the activation loop to include a significant reorientation of the catalytic domain (CD) relative to the apple-domain (AD) platform. The CD displays pronounced conformational heterogeneity; we identify three distinct conformers, suggesting that FXIa exists as a dynamic ensemble rather than a single rigid state. MD analysis indicates that activation disrupts the inter-CD allosteric communication present in the zymogen, thereby facilitating this flexibility. CD plasticity allows for the dynamic exposure of the A3 exosite, facilitating the binding of Factor IX. Comparison with plasma kallikrein (PKa) suggests that such structural flexibility may be a shared feature of apple-domain-containing contact-system proteases. Our results reveal that FXIa functions as a dynamic ensemble, providing a structural framework for understanding substrate recognition and identifying novel, non-catalytic sites for the development of specific FXIa inhibitors. Key Points - First apo cryo-EM structure of full-length FXIa reveals the unliganded active architecture and exposes the cryptic A3-domain FIX-binding exosite. - Three distinct apo-FXIa conformations and MD simulations reveal catalytic-domain flexibility during the transition from zymogen-like FXI to active FXIa.

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