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Title | Full-length αIIbβ3 cryo-EM structure reveals intact integrin initiate-activation intrinsic architecture. |
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Journal, issue, pages | Structure, Year 2024 |
Publish date | Mar 27, 2024 |
Authors | Tong Huo / Hongjiang Wu / Zeinab Moussa / Mehmet Sen / Valerie Dalton / Zhao Wang / |
PubMed Abstract | 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 ...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 links | Structure / PubMed:38579706 |
Methods | EM (single particle) |
Resolution | 2.97 - 3.12 Å |
Structure data | EMDB-29931, PDB-8gcd: EMDB-29932, PDB-8gce: |
Chemicals | ChemComp-CA: ChemComp-NAG: ChemComp-MG: ChemComp-HOH: |
Source |
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Keywords | CELL ADHESION / Integrin |