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首页> 外文期刊>Journal of Receptor, Ligand and Channel Research >Ligand competition assays indicate allosterism and insufficiency of the ternary complex model
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Ligand competition assays indicate allosterism and insufficiency of the ternary complex model

机译：配体竞争测定表明三元复合物模型的变构和不足

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Background: Many researchers have tried to correlate characteristics of ligand binding at G-protein–coupled receptor (GPCR) with ligand efficacy. The ternary complex model (TCM) is the traditional model for explaining the equilibrium of agonist-GPCR-G-protein interaction, and the effect of this interaction on agonist efficacy. However, no consistent correlation has been proven for various binding-efficacy data, so several extensions of the model have been proposed. These extensions are of descriptive value but their validity cannot be verified by binding-efficacy correlations. Therefore, we developed a novel approach to validate the TCM and its extensions.Methods: We simulated the predictions of the TCM for relationships within binding parameters. According to the TCM, an increase in the difference between high and low agonist affinities for a receptor (ie, greater KL/KH) should be accompanied by stability or an increase in the fraction of receptors bound to the agonist with high affinity (RH). To validate these predictions we performed ligand competition experiments for a set of ?2-adrenergic receptor (AR) agonists and analyzed the resulting binding data as well as data taken from relevant literature.Results: No smooth relationship exists between RH and KL/KH in our or others’ data, indicating the insufficiency of the TCM and its extensions. We introduce the allosteric modulators model as an alternative.Conclusions: To our knowledge, this is the first paper in which insufficiency of the TCM and its extensions based on binding data are shown, and the first in which the presence of allosteric modulators of ligand affinity is proven to be a necessity for explaining binding data at GPCRs.
机译：背景：许多研究人员试图将G蛋白偶联受体（GPCR）上的配体结合特征与配体功效相关联。三元复合物模型（TCM）是用于解释激动剂-GPCR-G-蛋白相互作用的平衡以及这种相互作用对激动剂功效的影响的传统模型。但是，对于各种结合效率数据，尚未证明一致的相关性，因此提出了该模型的几个扩展。这些扩展具有描述性的价值，但是它们的有效性不能通过结合功效相关性来验证。因此，我们开发了一种新颖的方法来验证TCM及其扩展。方法：我们模拟了TCM对绑定参数内关系的预测。根据TCM，对于受体的高和低激动剂亲和力之间差异的增加（即更大的KL / KH）应伴随稳定性或以高亲和力（RH）与激动剂结合的受体分数的增加。为了验证这些预测，我们对一组β2-肾上腺素能受体（AR）激动剂进行了配体竞争实验，并分析了所得结合数据以及相关文献中的数据。结果：RH和KL / KH之间不存在平滑关系我们或其他人的数据，表明中医及其扩展不足。结论：据我们所知，这是第一篇论文，其中显示了中医功能不足和基于结合数据的扩展，也是第一篇存在配体亲和力的别构调节剂的论文。被证明是解释GPCR结合数据的必要条件。

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