Transmembrane helical domain of the cannabinoid CB1 receptor.
Transmembrane helical domain of the cannabinoid CB1 receptor.
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大麻素 CB1 受体的跨膜螺旋结构域。
DOI：
10.1016/j.bpj.2008.12.3934
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发表时间：
2009
影响因子：
3.4
通讯作者：
Shim,Joong-Youn
中科院分区：
文献类型：
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作者：
Shim,Joong-Youn
脑大麻素（CB 1）受体是G蛋白偶联受体，属于视紫红质样亚家族。以β_2肾上腺素能受体（β_2AR）的X射线结构为模板，建立了CB_（1）受体失活状态的同源模型。我们使用105 ns的持续时间的分子动力学模拟的CB 1受体嵌入在1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）双层获得一些洞察CB 1受体的结构和功能。从均方根偏差结合详细的结构分析判断，CB 1受体的螺旋束似乎是完全收敛在50 ns的模拟。结果表明，CB 1受体的螺旋束结构保持拓扑结构非常相似的X-射线结构的G-蛋白偶联受体的整体。它还表明，CB 1受体是稳定的形成广泛的，水介导的H-键网络，芳香堆积相互作用，和受体-脂质相互作用的螺旋核心区域内。这些相互作用通常对功能基序（包括S（N）LAxAD、D（E）RY、CWxP和NPxxY基序）具有特异性，可能是对CB 1受体非活性状态施加的分子约束。看来，这些特定的相互作用的中断是必要的释放分子的约束，以实现适合G-蛋白激活的受体的构象变化。
Brain cannabinoid (CB1) receptors are G-protein coupled receptors and belong to the rhodopsin-like subfamily. A homology model of the inactive state of the CB1receptor was constructed using the x-ray structure ofβ2-adrenergic receptor (β2AR) as the template. We used 105 ns duration molecular-dynamics simulations of the CB1receptor embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer to gain some insight into the structure and function of the CB1receptor. As judged from the root mean-square deviations combined with the detailed structural analyses, the helical bundle of the CB1receptor appears to be fully converged in 50 ns of the simulation. The results reveal that the helical bundle structure of the CB1receptor maintains a topology quite similar to the x-ray structures of G-protein coupled receptors overall. It is also revealed that the CB1receptor is stabilized by the formation of extensive, water-mediated H-bond networks, aromatic stacking interactions, and receptor-lipid interactions within the helical core region. It is likely that these interactions, which are often specific to functional motifs, including the S(N)LAxAD, D(E)RY, CWxP, and NPxxY motifs, are the molecular constraints imposed on the inactive state of the CB1receptor. It appears that disruption of these specific interactions is necessary to release the molecular constraints to achieve a conformational change of the receptor suitable for G-protein activation.