Leukocyte Biology and Inflammation Laboratory, Structural Biology Program, Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.
Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2023 Jul 13;14(1):4168. doi: 10.1038/s41467-023-39763-0.
Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular signals ("inside-out" activation). Once bound, ligands drive proadhesive "outside-in" signaling. Anti-αIIbβ3 drugs like eptifibatide can engage the inactive integrin directly, inhibiting thrombosis but inadvertently impairing αIIbβ3 hemostatic functions. Bidirectional αIIbβ3 signaling is mediated by reorganization of the associated αIIb and β3 transmembrane α-helices, but the underlying changes remain poorly defined absent the structure of the full-length receptor. We now report the cryo-EM structures of full-length αIIbβ3 in its apo and eptifibatide-bound states in native cell-membrane nanoparticles at near-atomic resolution. The apo form adopts the bent inactive state but with separated transmembrane α-helices, and a fully accessible ligand-binding site that challenges the model that this site is occluded by the plasma membrane. Bound eptifibatide triggers dramatic conformational changes that may account for impaired hemostasis. These results advance our understanding of integrin structure and function and may guide development of safer inhibitors.
血小板整合素 αIIbβ3 保持弯曲的非活性状态（与生理配体的亲和力低），但可以响应细胞内信号迅速切换到配体竞争（高亲和力）状态（“内-外”激活）。一旦结合，配体就会驱动促黏附的“外-内”信号转导。像依替巴肽这样的抗-αIIbβ3 药物可以直接与非活性整合素结合，抑制血栓形成，但无意中会损害 αIIbβ3 的止血功能。双向 αIIbβ3 信号转导是通过相关的 αIIb 和 β3 跨膜 α-螺旋的重排介导的，但在没有全长受体结构的情况下，其潜在变化仍未得到很好的定义。我们现在报告了在天然细胞膜纳米颗粒中以近原子分辨率存在的全长 αIIbβ3 的apo 和依替巴肽结合状态的 cryo-EM 结构。apo 形式采用弯曲的非活性状态，但跨膜 α-螺旋分离，并且配体结合位点完全可及，这挑战了该位点被质膜阻塞的模型。结合的依替巴肽引发了剧烈的构象变化，这可能解释了止血功能受损的原因。这些结果推进了我们对整合素结构和功能的理解，并可能指导更安全抑制剂的开发。
