Full-length αIIbß3 CryoEM structure reveals intact integrin initiate-activation intrinsic architecture.

Integrin αIIbß3 is the key receptor regulating platelet retraction and accumulation, thus pivotal for hemostasis, and arterial thrombosis as well as a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the intact full-length αIIbß3, which covers three distinct states along the activation pathway. Here, we resolve intact αIIbß3 structure at 3Å resolution, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the head region ligand-binding domain tucked in a specific angle proximity to the TM region. In response to the addition of an Mn2+ agonist, we resolved two coexisting states, "intermediate" and "pre-active". Our structures show conformational changes of the intact αIIbß3 activating trajectory, as well as a unique twisting of the lower integrin legs representing intermediate state (TM region at a twisting conformation) integrin and a coexisting pre-active state (bent and opening in leg), which is required for inducing the transitioning platelets to accumulate. Our structure provides for the first time direct structural evidence for the lower legs' involvement in full-length integrin activation mechanisms. Additionally, our structure offers a new strategy to target the αIIbß3 lower leg allosterically instead of modulating the affinity of the αIIbß3 head region.