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首页> 外文期刊>Biochemistry >Probing the Structural Determinants for the Function of Intracellular Loop 2 in Structurally Cognate G-Protein-Coupled Receptors
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Probing the Structural Determinants for the Function of Intracellular Loop 2 in Structurally Cognate G-Protein-Coupled Receptors

机译：在结构同源的G蛋白偶联受体中探索细胞内环2功能的结构决定因素。

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Intracellular loop 2 (IL2) in G-protein-coupled receptors (GPCRs) is functionally important, e.g.,nin binding to G-protein and β-arrestin. Differences in secondary structure of IL2 in the crystal structures ofnthe very similar β1- and β2-adrenergic receptors (β1AR and β2AR, respectively), i.e., an R-helix and annL-shaped strand, respectively, emphasize the need to understand the structural basis for IL2 functionality.Wenstudied the properties of IL2 in the context of experimental data using aMonte Carlo-based ab initio method.nThe procedure was validated first by verifying that the IL2 structures in β1AR and β2AR crystals werencorrectly reproduced, even after conformational ensemble searches at >1200 K where most secondarynstructure had been lost. We found that IL2 in β1AR and β2AR sampled each other’s conformation butnadopted different energetically preferred conformations, consistent with the crystal structures. The resultsnindicate a persistent contextual preference for the structure of IL2, which was conserved when the IL2nsequences were interchanged between the receptors.We conclude that the protein environment,more than thenIL2 sequence, regulates the IL2 structures.We extended the approach to themolecularmodel of 5-HT2AR fornwhich no crystal structure is available and found that IL2 is predominantly helical, similar to IL2 in β1AR.nBecause the P3.57A mutation in IL2 had been shown to decrease β-arrestin binding and internalization, wenpredicted the effects of the mutation and found that it decreased the propensity of IL2 to form helix,nidentifying the helical IL2 as a component of the GPCR active form.
机译：G蛋白偶联受体（GPCR）中的细胞内环2（IL2）在功能上很重要，例如与G蛋白和β-arrestin的结合。在非常相似的β1-和β2-肾上腺素能受体（分别为β1AR和β2AR）的晶体结构中，IL2二级结构的差异，即分别为R-螺旋和anL形链，强调需要了解结构基础使用基于蒙特卡洛的从头算方法对实验数据中的IL2的性质进行了研究。n该程序首先通过验证β1AR和β2AR晶体中的IL2结构是否被正确复制而进行了验证，即使在>丢失了大部分二级结构的1200K。我们发现，β1AR和β2AR中的IL2相互采样了构象，但采用了不同的能量上优选的构象，与晶体结构一致。结果表明IL2结构具有持久的上下文偏好，当受体之间的IL2序列互换时，IL2结构得以保留。我们得出结论，蛋白质环境（而不是IL2序列）调节IL2结构。我们将方法扩展至5-分子模型HT2AR尚无可用的晶体结构，并且发现IL2主要是螺旋形的，类似于β1AR中的IL2.n由于已显示IL2中的P3.57A突变降低了β-arrestin的结合和内在化作用，因此预测了该突变的作用并发现它降低了IL2形成螺旋的倾向，从而确定螺旋IL2是GPCR活性形式的组成部分。

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  • 来源
    《Biochemistry》 |2010年第50期|p.10691-10701|共11页
  • 作者

    Jufang Shan Harel Weinstein and Ernest L. Mehler;

  • 作者单位

    ‡Department of Physiology and Biophysics and §The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute forComputational Biomedicine, Weill Cornell Medical College, Cornell University, New York, New York 10065, United States;

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