8UF7
Cryo-EM structure of POmAb, a Type-I anti-prothrombin antiphospholipid antibody, bound to kringle-1 of human prothrombin
Summary for 8UF7
| Entry DOI | 10.2210/pdb8uf7/pdb |
| EMDB information | 42185 |
| Descriptor | POmAb Light Chain, POmAb Heavy Chain, Prothrombin (3 entities in total) |
| Functional Keywords | autoimmunity, thrombosis, complex, immunoglobulin, coagulation factor, anticoagulation, inhibitor, blood clotting |
| Biological source | Mus musculus (mouse) More |
| Total number of polymer chains | 3 |
| Total formula weight | 112350.52 |
| Authors | Kumar, S.,Summers, B.,Basore, K.,Pozzi, N. (deposition date: 2023-10-03, release date: 2024-02-14, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 38437497DOI: 10.1182/blood.2023022942 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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