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TitleFull-length αIIbβ3 cryo-EM structure reveals intact integrin initiate-activation intrinsic architecture.
Journal, issue, pagesStructure, Vol. 32, Issue 7, Page 899-906.e3, Year 2024
Publish dateJul 11, 2024
AuthorsTong Huo / Hongjiang Wu / Zeinab Moussa / Mehmet Sen / Valerie Dalton / Zhao Wang /
PubMed AbstractIntegrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length ...Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3 Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show conformational changes of the αIIbβ3 activating trajectory and a unique twisting of the integrin legs, which is required for platelets accumulation. Our structure provides direct structural evidence for how the lower legs are involved in full-length integrin activation mechanisms and offers a new strategy to target the αIIbβ3 lower leg.
External linksStructure / PubMed:38579706 / PubMed Central
MethodsEM (single particle)
Resolution2.97 - 5.46 Å
Structure data

29931

8gcd

EMDB-29931, PDB-8gcd:
Full length Integrin AlphaIIbBeta3 in inactive state
Method: EM (single particle) / Resolution: 2.97 Å

29932

8gce

EMDB-29932, PDB-8gce:
The Extracellular Domain of Integrin AlphaIIbBeta3 in Intermediate State
Method: EM (single particle) / Resolution: 3.12 Å

EMDB-43046: Full length integrin AlphaIIbBeta3 in pre-active state
Method: EM (single particle) / Resolution: 5.46 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 / Integrin

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