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-Structure paper
| タイトル | Prothrombinase processivity is conferred by substrate allostery. |
|---|---|
| ジャーナル・号・ページ | EMBO J, Vol. 45, Issue 11, Page 3954-3977, Year 2026 |
| 掲載日 | 2026年4月22日 |
著者 | Fatma Işık Üstok / Alexandre Faille / Alan J Warren / James A Huntington / ![]() |
| PubMed 要旨 | 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 ...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'. |
リンク | EMBO J / PubMed:42020574 / PubMed Central |
| 手法 | EM (単粒子) / X線回折 |
| 解像度 | 2.8 - 3.1 Å |
| 構造データ | EMDB-56052, PDB-9tle: EMDB-56054, PDB-9tlg: ![]() PDB-9t00: |
| 化合物 | ![]() ChemComp-HOH: ![]() ChemComp-CA: ![]() ChemComp-NA: ![]() ChemComp-NAG: |
| 由来 |
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キーワード | BLOOD CLOTTING / enzyme / zymogen / complex / prothrombinase / factor Va / factor Xa / prothrombin / meizothrombin |
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