Cryo-EM structures of full-length integrin αIIbβ3 in native lipids
Abstract Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular signals (“inside-out” activation). Once bound, ligands drive proadhesive “outside-in” signali...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39763-0 |
| _version_ | 1797778785416773632 |
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| author | Brian D. Adair Jian-Ping Xiong Mark Yeager M. Amin Arnaout |
| author_facet | Brian D. Adair Jian-Ping Xiong Mark Yeager M. Amin Arnaout |
| author_sort | Brian D. Adair |
| collection | DOAJ |
| description | Abstract Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular signals (“inside-out” activation). Once bound, ligands drive proadhesive “outside-in” signaling. Anti-αIIbβ3 drugs like eptifibatide can engage the inactive integrin directly, inhibiting thrombosis but inadvertently impairing αIIbβ3 hemostatic functions. Bidirectional αIIbβ3 signaling is mediated by reorganization of the associated αIIb and β3 transmembrane α-helices, but the underlying changes remain poorly defined absent the structure of the full-length receptor. We now report the cryo-EM structures of full-length αIIbβ3 in its apo and eptifibatide-bound states in native cell-membrane nanoparticles at near-atomic resolution. The apo form adopts the bent inactive state but with separated transmembrane α-helices, and a fully accessible ligand-binding site that challenges the model that this site is occluded by the plasma membrane. Bound eptifibatide triggers dramatic conformational changes that may account for impaired hemostasis. These results advance our understanding of integrin structure and function and may guide development of safer inhibitors. |
| first_indexed | 2024-03-12T23:22:34Z |
| format | Article |
| id | doaj.art-b492d27f5ecf4a52879de123c3081790 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T23:22:34Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b492d27f5ecf4a52879de123c30817902023-07-16T11:22:01ZengNature PortfolioNature Communications2041-17232023-07-011411710.1038/s41467-023-39763-0Cryo-EM structures of full-length integrin αIIbβ3 in native lipidsBrian D. Adair0Jian-Ping Xiong1Mark Yeager2M. Amin Arnaout3Leukocyte Biology and Inflammation Laboratory, Structural Biology Program, Division of Nephrology, Department of Medicine, Massachusetts General HospitalLeukocyte Biology and Inflammation Laboratory, Structural Biology Program, Division of Nephrology, Department of Medicine, Massachusetts General HospitalThe Phillip and Patricia Frost Institute for Chemistry and Molecular Science, University of MiamiLeukocyte Biology and Inflammation Laboratory, Structural Biology Program, Division of Nephrology, Department of Medicine, Massachusetts General HospitalAbstract Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular signals (“inside-out” activation). Once bound, ligands drive proadhesive “outside-in” signaling. Anti-αIIbβ3 drugs like eptifibatide can engage the inactive integrin directly, inhibiting thrombosis but inadvertently impairing αIIbβ3 hemostatic functions. Bidirectional αIIbβ3 signaling is mediated by reorganization of the associated αIIb and β3 transmembrane α-helices, but the underlying changes remain poorly defined absent the structure of the full-length receptor. We now report the cryo-EM structures of full-length αIIbβ3 in its apo and eptifibatide-bound states in native cell-membrane nanoparticles at near-atomic resolution. The apo form adopts the bent inactive state but with separated transmembrane α-helices, and a fully accessible ligand-binding site that challenges the model that this site is occluded by the plasma membrane. Bound eptifibatide triggers dramatic conformational changes that may account for impaired hemostasis. These results advance our understanding of integrin structure and function and may guide development of safer inhibitors.https://doi.org/10.1038/s41467-023-39763-0 |
| spellingShingle | Brian D. Adair Jian-Ping Xiong Mark Yeager M. Amin Arnaout Cryo-EM structures of full-length integrin αIIbβ3 in native lipids Nature Communications |
| title | Cryo-EM structures of full-length integrin αIIbβ3 in native lipids |
| title_full | Cryo-EM structures of full-length integrin αIIbβ3 in native lipids |
| title_fullStr | Cryo-EM structures of full-length integrin αIIbβ3 in native lipids |
| title_full_unstemmed | Cryo-EM structures of full-length integrin αIIbβ3 in native lipids |
| title_short | Cryo-EM structures of full-length integrin αIIbβ3 in native lipids |
| title_sort | cryo em structures of full length integrin αiibβ3 in native lipids |
| url | https://doi.org/10.1038/s41467-023-39763-0 |
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