High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation
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.
Authors
- Gestur Vidarsson (ORCID: https://orcid.org/0000-0001-5621-003X)
- Coert Margadant (ORCID: https://orcid.org/0000-0002-5957-6683)
- Junichi Takagi (ORCID: https://orcid.org/0000-0002-1219-475X)
- C. Ellen van der Schoot (ORCID: https://orcid.org/0000-0002-8065-3540)
- Marcos Gragera (ORCID: https://orcid.org/0000-0002-3097-1743)
- Wendy Stam (ORCID: https://orcid.org/0000-0002-7470-847X)
- José M. de Pereda (ORCID: https://orcid.org/0000-0002-8912-6739)
- Eleftherios Zarkadas (ORCID: https://orcid.org/0000-0002-9276-9831)
- Francisco Javier Chichón (ORCID: https://orcid.org/0000-0003-2766-0327)
- Femke van der Meer
Institutions
- Leiden University (NL)
- Centre National de la Recherche Scientifique (FR)
- Utrecht University (NL)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Grenoble (FR)
- Sanquin (NL)
- Centro Nacional de Biotecnología (ES)
- Centro de Investigación del Cáncer (ES)
- Amsterdam University Medical Centers (NL)
- Protein Research Foundation (JP)
- Universidad Autónoma de Madrid (ES)
- University of Amsterdam (NL)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1126/sciadv.aed9833
- Primary Topic
- Platelet Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Landsteiner Foundation for Blood Transfusion Research
- European Regional Development Fund