Cryo-EM structures of full-length integrin αIIbβ3 in native lipids.
Cryo-EM structures of full-length integrin αIIbβ3 in native lipids.
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DOI：
10.1038/s41467-023-39763-0
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发表时间：
2023-07-13
影响因子：
16.6
通讯作者：
Arnaout, M. Amin
中科院分区：
文献类型：
--
作者：
Adair, Brian D. D.;Xiong, Jian-Ping;Yeager, Mark;Arnaout, M. Amin
血小板整联蛋白αIIbβ3维持在弯曲的非活性状态（对生理配体的低亲和力），但可响应细胞内信号（“由内而外”激活）迅速转换为配体活性（高亲和力）状态。一旦结合，配体驱动促粘附“由外向内”信号传导。抗αIIbβ3药物（如依替巴肽）可直接与非活性整合素结合，抑制血栓形成，但无意中损害αIIbβ3止血功能。双向αIIbβ3信号传导由相关αIIb和β3跨膜α-螺旋的重组介导，但在缺乏全长受体结构的情况下，潜在变化仍不明确。我们现在报告了近原子分辨率下天然细胞膜纳米颗粒中全长αIIbβ3在其apo和eptifibatide结合状态下的cryo-EM结构。载脂蛋白形式采用弯曲的非活性状态，但具有分离的跨膜α-螺旋和完全可及的配体结合位点，这挑战了该位点被质膜封闭的模型。结合的依替巴肽引发剧烈的构象变化，这可能是止血受损的原因。这些结果推进了我们对整合素结构和功能的理解，并可能指导更安全的抑制剂的开发。整合素信号在健康和疾病中的结构基础尚未完全理解。在这里，作者确定了天然膜环境中全长血小板整合素αIIbβ3在其apo和eptifibatide结合构象中的cryoEM结构。
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. The structural basis of integrin signaling in health and disease is not fully understood. Here, the authors determine the cryoEM structure of full-length platelet integrin αIIbβ3 in its apo and eptifibatide-bound conformations in a native membrane environment.
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DOI：
10.1111/j.1538-7836.2009.03360.x
发表时间：
2009-06
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Aster RH;Curtis BR;McFarland JG;Bougie DW
通讯作者：
Bougie DW
影响因子：
3.4
作者：
Matsumoto, Atsushi;Kamata, Tetsuji;Yura, Kei
通讯作者：
Yura, Kei
影响因子：
6.1
作者：
Afonine PV;Grosse-Kunstleve RW;Chen VB;Headd JJ;Moriarty NW;Richardson JS;Richardson DC;Urzhumtsev A;Zwart PH;Adams PD
通讯作者：
Adams PD
影响因子：
3.8
作者：
Ginsberg MH
通讯作者：
Ginsberg MH
影响因子：
120.1
作者：
Ley, Klaus;Rivera-Nieves, Jesus;Shattil, Sanford
通讯作者：
Shattil, Sanford