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TitleCryo-EM structures of full-length integrin αIIbβ3 in native lipids.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4168, Year 2023
Publish dateJul 13, 2023
AuthorsBrian D Adair / Jian-Ping Xiong / Mark Yeager / M Amin Arnaout /
PubMed AbstractPlatelet 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 ...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.
External linksNat Commun / PubMed:37443315 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.4 Å
Structure data

EMDB-40988, PDB-8t2u:
Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Native Lipids complexed with Eptifibatide
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-40989, PDB-8t2v:
Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Native Lipids
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • human (human)
  • synthetic construct (others)
KeywordsCELL ADHESION / complex / open headpiece

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