8R8D
Cryo-EM structure of coagulation factor beta-XIIa in complex with the garadacimab Fab fragment (symmetric dimer)
Summary for 8R8D
| Entry DOI | 10.2210/pdb8r8d/pdb |
| EMDB information | 18999 |
| Descriptor | Coagulation factor XII, Garadacimab heavy chain variable region, Garadacimab light chain variable region, ... (5 entities in total) |
| Functional Keywords | complex, coagulation, trypsin-like serine protease, hereditary angioedema (hae), blood clotting |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 150954.34 |
| Authors | Drulyte, I. (deposition date: 2023-11-29, release date: 2023-12-13, Last modification date: 2024-10-16) |
| Primary citation | Drulyte, I.,Ghai, R.,Ow, S.Y.,Kapp, E.A.,Quek, A.J.,Panousis, C.,Wilson, M.J.,Nash, A.D.,Pelzing, M. Structural basis for the inhibition of beta FXIIa by garadacimab. Structure, 32:1705-, 2024 Cited by PubMed Abstract: Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. PubMed: 39059382DOI: 10.1016/j.str.2024.07.001 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.6 Å) |
Structure validation
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