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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Two distinct conformations of helix 6 observed in antagonist-bound structures of a β_1-adrenergic receptor
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Two distinct conformations of helix 6 observed in antagonist-bound structures of a β_1-adrenergic receptor

机译：在β_1-肾上腺素能受体的拮抗剂结合结构中观察到两个不同的螺旋6构象

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摘要

The β_1-adrenergic receptor (β_1AR) is a G-protein-coupled receptor whose inactive state structure was determined using a thermosta-bilized mutant (β_1AR-M23). However, it was not thought to be in a fully inactivated state because there was no salt bridge between Arg139 and Glu285 linking the cytoplasmic ends of transmembrane helices 3 and 6 (the R~(3.50) - D/E~(6.30) "ionic lock"). Here we compare eight new structures of β_1AR-M23, determined from crystallogra-phically independent molecules in four different crystals with three different antagonists bound. These structures are all in the inactive R state and show clear electron density for cytoplasmic loop 3 linking transmembrane helices 5 and 6 that had not been seen previously. Despite significantly different crystal packing interactions, there are only two distinct conformations of the cytoplasmic end of helix 6, bent and straight. In the bent conformation, the Arg139-Glu285 salt bridge is present, as in the crystal structure of dark-state rhodopsin. The straight conformation, observed in previously solved structures of β-receptors, results in the ends of helices 3 and 6 being too far apart for the ionic lock to form. In the bent conformation, the R~(3.50) - E~(6.30) distance is significantly longer than in rhodopsin, suggesting that the interaction is also weaker, which could explain the high basal activity in β_1AR compared to rhodopsin. Many mutations that increase the constitutive activity of G-protein-coupled receptors are found in the bent region at the cytoplasmic end of helix 6, supporting the idea that this region plays an important role in receptor activation.
机译：β_1肾上腺素能受体（β_1AR）是一种G蛋白偶联受体，其失活状态结构是通过热稳定化突变体（β_1AR-M23）确定的。然而，它不被认为处于完全灭活状态，因为在Arg139和Glu285之间没有盐桥连接跨膜螺旋3和6（R〜（3.50）-D / E〜（6.30）锁”）。在这里，我们比较了β_1AR-M23的八个新结构，这些结构是由晶体学上独立的分子在四个具有三个不同拮抗剂结合的不同晶体中确定的。这些结构都处于非活性R状态，对于连接跨膜螺旋5和6的胞质环3来说，显示出清晰的电子密度，这是以前从未见过的。尽管晶体堆积相互作用显着不同，但螺旋6的胞质末端只有两个截然不同的构象：弯曲和笔直。在弯曲构象中，存在Arg139-Glu285盐桥，就像在暗态视紫红质的晶体结构中一样。在先前解析的β受体结构中观察到的笔直构象导致螺旋3和6的末端相距太远，无法形成离子锁。在弯曲构象中，R〜（3.50）-E〜（6.30）的距离显着长于视紫红质，这表明相互作用也较弱，这可以解释β_1AR中视视紫红质的高基础活性。在螺旋6的细胞质末端的弯曲区域发现了许多增加G蛋白偶联受体组成活性的突变，支持了这一区域在受体激活中起重要作用的想法。

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