Efficacy of the β₂-adrenergic receptor is determined by conformational equilibrium in the transmembrane region.
Efficacy of the β₂-adrenergic receptor is determined by conformational equilibrium in the transmembrane region.
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DOI：
10.1038/ncomms2046
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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许多靶向G蛋白偶联受体（GPCRs）的药物以不同的强度诱导或抑制其信号转导，从而影响其治疗特性。然而，信号传导水平差异的机制仍然不清楚，尽管可以获得通过X射线晶体学确定的与配体复合的GPCR的几种结构。在此，我们利用NMR监测β2-肾上腺素能受体（β2AR）中性拮抗剂和部分激动剂结合状态下82位蛋氨酸残基的信号，这些信号与活化后跨膜区的构象变化相关。我们发现，这个残基存在于逆激动剂结合状态和完全激动剂结合状态之间的构象平衡，后者的人口反映了在每个配体结合状态的信号转导水平。这些发现为深入了解β 2 AR和其他GPCR的多水平信号传导，包括基础活性，以及GPCR介导的信号转导机制提供了新的见解。有许多药物靶向β-肾上腺素能受体，但它们具有不同的功效。Kofuku等人使用NMR显示跨膜结构域中的甲硫氨酸82经历构象变化，这取决于结合的是激动剂还是反向激动剂，从而解释了不同的药物功效。
Many drugs that target G-protein-coupled receptors (GPCRs) induce or inhibit their signal transduction with different strengths, which affect their therapeutic properties. However, the mechanism underlying the differences in the signalling levels is still not clear, although several structures of GPCRs complexed with ligands determined by X-ray crystallography are available. Here we utilized NMR to monitor the signals from the methionine residue at position 82 in neutral antagonist- and partial agonist-bound states of β2-adrenergic receptor (β2AR), which are correlated with the conformational changes of the transmembrane regions upon activation. We show that this residue exists in a conformational equilibrium between the inverse agonist-bound states and the full agonist-bound state, and the population of the latter reflects the signal transduction level in each ligand-bound state. These findings provide insights into the multi-level signalling of β2AR and other GPCRs, including the basal activity, and the mechanism of signal transduction mediated by GPCRs. Many drugs exist that target the β-adrenergic receptor, but they have different efficacies. Kofuku et al. use NMR to show that methionine 82 in the transmembrane domain undergoes conformational changes depending on whether agonists or inverse agonists are bound, explaining the differential drug efficacy.
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影响因子：
3.3
作者：
Hanania NA;Dickey BF;Bond RA
通讯作者：
Bond RA
DOI：
10.1126/science.1215802
发表时间：
2012-03-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Liu JJ;Horst R;Katritch V;Stevens RC;Wüthrich K
通讯作者：
Wüthrich K
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.4
作者：
Gether, U;Lin, S;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
64.8
作者：
Choe, Hui-Woog;Kim, Yong Ju;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.