PDF(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 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 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.
摘要：
整合素αIIbβ3是调节血小板收缩和积累的关键受体，是抗血栓治疗的公认药物靶标。在这里，我们解析了全长αIIbβ3的低温-EM结构，该结构涵盖了激活途径中的三种不同状态。首先,我们在非活动状态下获得了3µ分辨率的αIIbβ3结构，揭示了异源二聚体的整体拓扑结构，其中跨膜（TM）螺旋和配体结合结构域以特定角度靠近TM区域。加入Mn2+激动剂后，我们解析了两个共存结构，表示非活动状态和活动状态之间的两个新状态。我们的结构显示了αIIbβ3激活轨迹的构象变化和整合素腿的独特扭曲，这是血小板积累所必需的。我们的结构为小腿如何参与全长整合素激活机制提供了直接的结构证据，并提供了靶向αIIbβ3小腿的新策略。
