Ligand Selectivity of D2 Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding
Ligand Selectivity of D2 Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding
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DOI：
10.1124/jpet.108.141531
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Schetz, John A.
中科院分区：
文献类型：
--
作者：
Ericksen, Spencer S.;Cummings, David F.;Schetz, John A.
我们发现了D-2多巴胺受体对生理相关钠浓度（140 mM）的显着变构反应，其特征是钠增强了对d -4选择性激动剂和拮抗剂的结合亲和力。这种增强在D-2-V2.61(91) F突变体中更为明显，并且不能被同等浓度的钠替代阳离子n -甲基- d -氨基葡萄糖所模仿。通过分析钠结合对D-2受体模型构建物动力学特性的影响，在分子水平上对这一现象进行了计算探索。正态分析确定了一种模式（M-19），它参与结合间隙的开/闭运动，对钠效应特别敏感。为了研究对D-2受体配体识别的影响，将其中一种配体L-745,870[3-{[4-（4-氯苯基）哌嗪-1-基]甲基}- 1h -吡咯[2,3-b]吡啶或CPPMA，氯苯基哌嗪基甲基苄啶]沿M-19轨迹对接到构象中。结构上和药理学上已经建立的配体-受体相互作用，包括与D3.32（114）的离子相互作用以及配体芳基部分与V2.61(91) F之间的相互作用，仅在“开放”相构象中实现。（-）-raclopride[3,5-二氯- n-（1-乙基吡咯烷-2-基甲基）- 2-羟基-6-甲氧基苯酰胺]的对接表明，在钠结合扰动下，相同的结合间隙变化也解释了野生型D-2受体对取代苯酰胺的结合亲和力增强。我们的研究结果证明了关键的相互作用是如何通过在变构位点的占有来调节的，并且与钠结合通过动态变化增加取代苯酰胺和1,4- dap配体对正构位点的接近性以及1,4- dap对V2.61(91) F的接近性来增强所选配体的亲和力的机制是一致的。
We have uncovered a significant allosteric response of the D-2 dopamine receptor to physiologically relevant concentrations of sodium (140 mM), characterized by a sodium-enhanced binding affinity for a D-4-selective class of agonists and antagonists. This enhancement is significantly more pronounced in a D-2-V2.61(91) F mutant and cannot be mimicked by an equivalent concentration of the sodium replacement cation N-methyl-D-glucamine. This phenomenon was explored computationally at the molecular level by analyzing the effect of sodium binding on the dynamic properties of D-2 receptor model constructs. Normal mode analysis identified one mode (M-19), which is involved in the open/closed motions of the binding cleft as being particularly sensitive to the sodium effect. To examine the consequences for D-2 receptor ligand recognition, one of the ligands, L-745,870 [3-{[4-(4- chlorophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine or CPPMA, chlorophenylpiperazinyl methylazaindole], was docked into conformers along the M-19 trajectory. Structurally and pharmacologically well established ligand-receptor interactions, including the ionic interaction with D3.32(114) and interactions between the ligand aryl moieties and V2.61(91) F, were achieved only in "open" phase conformers. The docking of (-)-raclopride [3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)- 2-hydroxy-6-methoxybenzamide] suggests that the same binding cleft changes in response to sodium-binding perturbation account as well for the enhancements in binding affinity for substituted benzamides in the wild-type D-2 receptor. Our findings demonstrate how key interactions can be modulated by occupancy at an allosteric site and are consistent with a mechanism in which sodium binding enhances the affinity of selected ligands through dynamic changes that increase accessibility of substituted benzamides and 1,4-DAP ligands to the orthosteric site and accessibility of 1,4-DAPs to V2.61(91) F.