8UF7

Cryo-EM structure of POmAb, a Type-I anti-prothrombin antiphospholipid antibody, bound to kringle-1 of human prothrombin

8UF7 の概要

• エントリーDOI: 10.2210/pdb8uf7/pdb
• EMDBエントリー: 42185
• 分子名称: POmAb Light Chain, POmAb Heavy Chain, Prothrombin (3 entities in total)
• 機能のキーワード: autoimmunity, thrombosis, complex, immunoglobulin, coagulation factor, anticoagulation, inhibitor, blood clotting
• 由来する生物種: Mus musculus (mouse); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 112350.52

構造登録者

Kumar, S.,Summers, B.,Basore, K.,Pozzi, N. (登録日: 2023-10-03, 公開日: 2024-02-14, 最終更新日: 2025-05-14)

主引用文献

Kumar, S.,Summers, B.,Basore, K.,Pengo, V.,Flaumenhaft, R.,Pozzi, N.
Cryo-EM structure and functional basis of prothrombin recognition by a type I antiprothrombin antiphospholipid antibody.
Blood, 143:2005-2011, 2024

PubMed Abstract: Antiprothrombin antibodies are found in antiphospholipid patients, but how they interact with prothrombin remains elusive. Prothrombin adopts closed and open forms. We recently discovered type I and type II antibodies and proposed that type I recognizes the open form. In this study, we report the discovery and structural and functional characterization in human plasma of a type I antibody, POmAb (prothrombin open monoclonal antibody). Using surface plasmon resonance and single-molecule spectroscopy, we show that POmAb interacts with kringle-1 of prothrombin, shifting the equilibrium toward the open form. Using single-particle cryogenic electron microscopy (cryo-EM), we establish that the epitope targeted by POmAb is in kringle-1, comprising an extended binding interface centered at residues R90-Y93. The 3.2-Å cryo-EM structure of the complex reveals that the epitope overlaps with the position occupied by the protease domain of prothrombin in the closed state, explaining the exclusive binding of POmAb to the open form. In human plasma, POmAb prolongs phospholipid-initiated and diluted Russell's viper venom clotting time, which could be partly rescued by excess phospholipids, indicating POmAb is an anticoagulant but exerts a weak lupus anticoagulant effect. These studies reveal the structural basis of prothrombin recognition by a type I antiphospholipid antibody and uncover an exciting new strategy to achieve anticoagulation in human plasma.

PubMed: 38437497
DOI: 10.1182/blood.2023022942

実験手法

ELECTRON MICROSCOPY (3.2 Å)