Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation
Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation
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DOI：
10.1016/j.bpj.2019.10.007
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发表时间：
2020-02-25
影响因子：
3.4
通讯作者：
Filizola, Marta
中科院分区：
文献类型：
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作者：
Hu, Xiaohu;Provasi, Davide;Filizola, Marta
在阿片类药物滥用流行的时代，人们越来越需要了解阿片受体如何被变构调节，以指导更有效和更安全的阿片类药物治疗的发展。μ-阿片样物质（MOP）受体是大多数临床使用的阿片类药物的药理学靶标，其调节剂是单价和二价阳离子。具体而言，几十年来已知单价钠阳离子（Na+）通过减少激动剂结合来影响MOP受体信号传导，而二价镁阳离子（Mg 2+）已显示出具有相反的作用，尽管存在氯化钠。尽管超高分辨率阿片受体晶体结构揭示了特定的Na+结合位点，并且分子动力学（MD）模拟研究支持这种单价离子通过稳定受体非活性状态来降低激动剂结合的观点，但MOP受体上Mg 2+的推定结合位点以及负责其受体正变构调节的分子决定因素尚不清楚。在这项工作中，我们进行了几十微秒的全原子分子动力学模拟，以调查的同时绑定的Mg 2+和Na+阳离子的MOP受体嵌入在一个明确的脂水环境中的非活性和活性的晶体结构，并确认足够的采样Mg 2+离子结合与巨正则蒙特卡罗分子动力学方法。这些模拟的分析揭示了1）Mg 2+在MOP受体上的优选结合位点，2）Mg 2+和Na+阳离子之间竞争特定位点的细节，3）结合亲和力的估计，以及4）Mg 2+阳离子对MOP受体的正变构调节的分子机制的可检验假设。
In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the mu-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, are monovalent and divalent cations. Specifically, the monovalent sodium cation (Na+) has been known for decades to affect MOP receptor signaling by reducing agonist binding, whereas the divalent magnesium cation (Mg2+) has been shown to have the opposite effect, notwithstanding the presence of sodium chloride. Although ultra-high-resolution opioid receptor crystal structures have revealed a specific Na+ binding site and molecular dynamics (MD) simulation studies have supported the idea that this monovalent ion reduces agonist binding by stabilizing the receptor inactive state, the putative binding site of Mg2+ on the MOP receptor, as well as the molecular determinants responsible for its positive allosteric modulation of the receptor, are unknown. In this work, we carried out tens of microseconds of all-atom MD simulations to investigate the simultaneous binding of Mg2+ and Na+ cations to inactive and active crystal structures of the MOP receptor embedded in an explicit lipid-water environment and confirmed adequate sampling of Mg2+ ion binding with a grand canonical Monte Carlo MD method. Analyses of these simulations shed light on 1) the preferred binding sites of Mg2+ on the MOP receptor, 2) details of the competition between Mg2+ and Na+ cations for specific sites, 3) estimates of binding affinities, and 4) testable hypotheses of the molecular mechanism underlying the positive allosteric modulation of the MOP receptor by the Mg2+ cation.