Structural insights into the exosite-mediated activation of Factor IX by Factor XIa using cryo-EM.

Authors

Bassem M Mohammed, Samantha Deavila, Tristan Friet, Isabella Dattilio

Published in

Journal of thrombosis and haemostasis : JTH. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Factor XI (FXI) occupies a unique and clinically significant niche, bridging the tissue factor-driven and contact-driven coagulation pathways. Irrespective of the trigger, activated factor XI (FXIa) contributes to clotting by activating factor IX (FIX). Biochemical studies established that this reaction requires the membrane-binding FIX-Gla domain to engage an exosite on the FXIa Apple 3 (A3) domain, that only become available upon FXI activation. Structural data for FXIa, FIX, FIXaβ, and the FXIa:FIX complex are lacking; current understanding relies on zymogen FXI crystal structures and homology modeling of FXIa after kallikrein.
Elucidate the high-resolution structure of FXIa in functionally relevant conformation in complex with FIX.
We utilized cryogenic electron microscopy (cryo-EM) to determine the structures of human FXIa in complex with its full-length substrate, FIX, and activated product, FIXaβ.
We report the first cryo-EM structures of FXIa in complex with its substrate, FIX, and activated FIX (FIXaβ). The structures capture a functionally relevant conformational change in the FXIa catalytic domain and reveals the first view of the entire FIX and FIXaβ. Critically, we visualize the FIX-Gla domain precisely docked to the FXIa-A3 exosite on both subunits of the FXIa dimer. We also define the first step of proteolysis, visualizing the FIX Arg145 inserted into the primary specificity pocket of FXIa.
The structures define the full FXIa:FIX interface providing a structural template for understanding the sequential activation of FIX and for developing a new class of selective allosteric antithrombotic agents.

PMID:
42628751
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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