Structural Superimposition

Abstact

Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by 'bent/closed' to 'extended/open' conformational changes. Integrin alphaIIbbeta3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on beta3 is recognized by pregnancy-associated maternal alloantibodies, potentially causing fetal/neonatal alloimmune thrombocytopenia (FNAIT) and even intracranial hemorrhage or perinatal death. We report the structure of an anti-HPA-1a antibody fragment (Fab 26.4) in complex with integrin alphaIIbbeta3 at high resolution by cryo-electron microscopy. Fab 26.4 binding locks alphaIIbbeta3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits alphaIIbbeta3-dependent fibrinogen binding and platelet aggregation. Thus, anti-HPA-1a antibodies directly impair integrin activation by preventing required conformational changes. These insights will improve FNAIT diagnostics and treatment, and spark the development of novel allosteric inhibitors against beta3 integrins for future therapeutic applications.