Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
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DOI：
10.1038/nature02976
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发表时间：
2004-11-04
期刊：
影响因子：
64.8
通讯作者：
Springer, TA
中科院分区：
文献类型：
--
作者：
Xiao, T;Takagi, J;Springer, TA
整合素是所有后生动物中重要的粘附受体，可跨膜双向传递构象变化。整合素α和β亚基在胞外域中形成一个头和两个长腿并跨越膜。在这里，我们用晶体结构定义了整联蛋白胞外域的构象和配体亲和力的变构调节的原子基础，以及纤维蛋白原模拟疗法如何与血小板整联蛋白α(IIb)β(3)结合。 beta(3)I 结构域中的变构改变了三个金属结合位点、相关环以及 alpha1 和 alpha7 螺旋。 α7 螺旋的活塞式位移导致 β(3)I 和混合结构域之间发生 62 度重新定向。通过上β(3)腿中刚性连接的丛蛋白/信号蛋白/整合素(PSI)结构域的传输导致α腿和β腿的膝盖之间有70埃的分离。因此，头部的变构破坏了先前描述的低亲和力弯曲整合素构象中的腿之间的相互作用，并且腿伸展将高亲和力头部定位在细胞表面之上。
Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin alpha and beta subunits form a head and two long legs in the ectodomain and span the membrane. Here, we define with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen- mimetic therapeutics bind to platelet integrin alpha(IIb)beta(3). Allostery in the beta(3)I domain alters three metal binding sites, associated loops and alpha1- and alpha7-helices. Piston-like displacement of the alpha7-helix causes a 62degrees reorientation between the beta(3)I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin ( PSI) domain in the upper beta(3) leg causes a 70 Angstrom separation between the knees of the alpha and beta legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.