Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity.
Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity.
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DOI：
10.1111/j.1747-0285.2012.01390.x
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发表时间：
2012-08
影响因子：
3
通讯作者：
Tikhonova IG
中科院分区：
文献类型：
--
作者：
Selvam B;Wereszczynski J;Tikhonova IG
从分子动力学角度探讨β1和β2肾上腺素受体拮抗剂解结合的分子机制，为进一步研究配体亚型和亚种选择性提供可能。我们模拟了β1-选择性艾司洛尔和β2-选择性ICI-118551从两种受体到细胞外环境的解结合，并发现了不同的解结合分子特征。通过计算功谱，我们发现受体之间对拮抗剂解结合途径有不同的偏好，特别是在β1受体中，垂直于膜的途径是有利的，而在β2受体中，涉及螺旋5、6和7的侧向途径是有利的。基于优选途径估计的解结合自由能变化与实验配体选择性相关。然后，我们发现非保守的K347（6.58）似乎有助于通过β1肾上腺素受体中的氢键将艾司洛尔引导至细胞外表面。相反，疏水和芳香相互作用在驱动ICI-118551通过β2肾上腺素受体中最简单的途径中占主导地位。我们展示了我们的研究如何刺激选择性拮抗剂的设计，并讨论了配体选择性的其他可能的分子原因，包括激动剂的顺序结合和受体细胞外表面的糖基化。
From the molecular mechanism of antagonist unbinding in the β1 and β2 adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of β1-selective Esmolol and β2-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the β1 adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the β2 adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the β1 adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the β2 adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface.
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影响因子：
56.9
作者：
Grubmuller, H;Heymann, B;Tavan, P
通讯作者：
Tavan, P
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.91.9.4024
发表时间：
1994-04-26
影响因子：
11.1
作者：
KAUSHAL, S;RIDGE, KD;KHORANA, HG
通讯作者：
KHORANA, HG
影响因子：
3.6
作者：
Isogaya, M;Sugimoto, Y;Kurose, H
通讯作者：
Kurose, H
影响因子：
3.6
作者：
Hoffmann, C;Leitz, MR;Klotz, KN
通讯作者：
Klotz, KN