Two-state models and the analysis of the allosteric effect of gallamine at the M2 muscarinic receptor
Two-state models and the analysis of the allosteric effect of gallamine at the M2 muscarinic receptor
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DOI：
10.1124/jpet.108.136960
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Griffin, Michael T.
中科院分区：
文献类型：
--
作者：
Ehlert, Frederick J.;Griffin, Michael T.
我们测量的功能反应和选定的激动剂在M-2毒蕈碱受体的结合特性的影响，并分析了变构三元复合物模型的背景下的数据。我们的分析表明，没食子胺修饰激动剂亲和力而不影响疗效。为了解释这种行为，我们研究了变构三元复合物模型在更深层次的分析，以评估变构的差异亲和力的镓胺的地面和活性状态的受体。我们的模拟结果表明，两个国家的模型的基础上一个单一的正构位点的激动剂连接到一个别构网站的加拉胺不能占亲和力只调制，即使考虑多种构象的地面和活性状态。我们还在变构三元复合物模型的背景下扩展了串联双位点模型（J Biol Chem 275：18836-18844，2000），并在受体状态水平上分析了所得的混合模型。该模型假定激动剂首先结合到中继位点，然后穿梭到激活位点以打开受体。如果假设变构发生在中继位点而不是活化位点，则该模型可以以与变构三元复合物模型一致的方式解释仅亲和力调节。
We measured the influence of gallamine on the functional responses and binding properties of selected agonists at the M-2 muscarinic receptor and analyzed the data within the context of the allosteric ternary complex model. Our analysis showed that gallamine modified agonist affinity without influencing efficacy. To explain this behavior, we investigated the allosteric ternary complex model at a deeper level of analysis to assess allosterism in terms of the differential affinity of gallamine for ground and active states of the receptor. Our simulations showed that two-state models based on a single orthosteric site for the agonist linked to an allosteric site for gallamine could not account for affinity-only modulation, even if multiple conformations of ground and active states were considered. We also expanded the tandem two-site model (J Biol Chem 275: 18836-18844, 2000) within the context of the allosteric ternary complex model and analyzed the resulting hybrid model at the level of receptor states. This model posits that the agonist first binds to a relay site and then shuttles to the activation site to turn on the receptor. If it is assumed that allosterism occurs at the relay site and not the activation site, then this model can account for affinity- only modulation in a manner consistent with the allosteric ternary complex model.