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TitleHigh-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation.
Journal, issue, pagesSci Adv, Vol. 12, Issue 29, Page eaed9833, Year 2026
Publish dateJul 17, 2026
AuthorsJosé M de Pereda / Wendy Stam / Marcos Gragera / Femke van der Meer / Francisco J Chichón / Eleftherios Zarkadas / Ellen van der Schoot / Gestur Vidarsson / Junichi Takagi / Coert Margadant /
PubMed AbstractIntegrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by 'bent/closed' to 'extended/open' conformational changes. Integrin αIIbβ3, being crucial for ...Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by 'bent/closed' to 'extended/open' conformational changes. Integrin αIIbβ3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on β3 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 αIIbβ3 at high resolution by cryo-electron microscopy. Fab 26.4 binding locks αIIbβ3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits αIIbβ3-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 β3 integrins for future therapeutic applications.
External linksSci Adv / PubMed:42467762 / PubMed Central
MethodsEM (single particle)
Resolution2.64 Å
Structure data

55800

9td2

EMDB-55800, PDB-9td2:
Integrin AlphaIIbBeta3 bound to Fab of the anti-HPA-1a antibody 26.4
Method: EM (single particle) / Resolution: 2.64 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsCELL ADHESION / Human Platelet Antigen / FNAIT / alloantibody / cryo-EM

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