9TLG

Structure of human prothrombinase with meizothrombin

Summary for 9TLG

• Entry DOI: 10.2210/pdb9tlg/pdb
• Related: 9I2H
• EMDB information: 56054
• Descriptor: Coagulation factor V heavy chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (12 entities in total)
• Functional Keywords: prothrombinase, factor va, factor xa, meizothrombin, blood clotting
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 267092.79

Authors

Faille, A.,Ustok, F.I.,Warren, A.,Huntingon, J.A. (deposition date: 2025-12-10, release date: 2026-08-12)

Primary citation

Ustok, F.I.,Faille, A.,Warren, A.J.,Huntington, J.A.
Prothrombinase processivity is conferred by substrate allostery.
Embo J., 45:3954-3977, 2026

PubMed Abstract: The prothrombinase complex, comprised of factor (f) Xa and fVa, converts prothrombin to thrombin through sequential cleavage at two sites in a rapid and processive manner. The molecular basis of prothrombin processing is an enzymatical mystery that to solve requires structural insight into how the substrate and intermediate bind to prothrombinase. Here we present two 3.1 Å cryo-EM structures of prothrombinase bound to prothrombin and to meizothrombin. The prothrombin complex revealed a surprising interaction between the end of the heavy chain of fVa with exosite I of prothrombin, accounting for 70% of the contact interface. Triggering of the zymogen-to-protease conformational change following cleavage at Arg320 alters all domain-domain and fVa interactions observed for prothrombin, and results in a large-scale rearrangement of meizothrombin that presents the second cleavage site (Arg271) for processing. Together, these structures reveal a remarkable enzymatic mechanism that requires the active participation of the substrate itself, and introduces a new paradigm of 'substrate allostery'.

PubMed: 42020574
DOI: 10.1038/s44318-026-00782-4

Experimental method

ELECTRON MICROSCOPY (3.1 Å)