Full-length αIIbβ3 CryoEM structure reveals intact integrin initiate-activation intrinsic architecture

Abstract

Integrin IIb{beta}3 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 IIb{beta}3, which covers three distinct states along the activation pathway. Here, we resolve intact IIb{beta}3 structure at 3[A] 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 a Mn2+ agonist, we resolved two coexisting states, "intermediate" and "pre-active". Our structures show conformational changes of the intact IIb{beta}3 activating trajectory, as well as a unique twisting of the lower integrin legs representing an intermediate state (TM region at a twisting conformation) 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 IIb{beta}3 lower leg allosterically instead of modulating the affinity of the IIb{beta}3 head region.