Language
English
Publication Date
7-11-2024
Journal
Structure
DOI
10.1016/j.str.2024.03.006
PMID
38579706
PMCID
PMC11246237
PubMedCentral® Posted Date
7-11-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3Å 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 Mn2+ 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.
Keywords
Humans, Binding Sites, Cryoelectron Microscopy, Manganese, Models, Molecular, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Binding, Protein Conformation, Protein Multimerization, Integrin beta3, Integrin alpha2
Published Open-Access
yes
Recommended Citation
Huo, Tong; Wu, Hongjiang; Moussa, Zeinab; et al., "Full-Length αIIbβ3 Cryo-EM Structure Reveals Intact Integrin Initiate-Activation Intrinsic Architecture" (2024). Faculty and Staff Publications. 4938.
https://digitalcommons.library.tmc.edu/baylor_docs/4938
Graphical Abstract
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons