Identification of essential cannabinoid-binding domains: structural insights into early dynamic events in receptor activation.
Identification of essential cannabinoid-binding domains: structural insights into early dynamic events in receptor activation.
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重要大麻素结合域的识别：受体激活早期动态事件的结构见解。
DOI：
10.1074/jbc.m111.261651
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Kendall,DebraA
中科院分区：
文献类型：
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作者：
Shim,Joong-Youn;Bertalovitz,AlexanderC;Kendall,DebraA
经典的大麻素激动剂HU 210是（−）-Δ9-四氢大麻酚的结构类似物，与脑大麻素（CB 1）受体结合并激活信号转导途径。迄今为止，还没有CB 1受体的确切分子描述。利用CB 1受体的次要结合口袋作为主要配体相互作用位点，我们使用脂质双层分子动力学（MD）模拟探索了HU 210结合。在潜在的配体接触残基中，我们通过突变分析鉴定了残基Phe-1742.61、Phe-1772.64、Leu-1933.29和Met-3636.55为HU 210结合的关键残基。使用这些残基来指导模拟，我们确定了CB 1受体中必需的大麻素结合结构域，包括对经典和非经典大麻素的C3烷基链结合重要的疏水口袋。分析HU 210-CB 1受体复合物、CP 55940-CB 1受体复合物和（−）-Δ9-四氢大麻酚-CB 1受体复合物的模拟，我们发现C3烷基链的位置和Trp-3566.48和Trp-2795.43之间的芳香堆积对于Trp-3566.48旋转异构体通过刚性-H6的身体运动。突变体受体的功能数据表明G蛋白活化效力的降低与HU 210配体结合亲和力的降低相似。
The classical cannabinoid agonist HU210, a structural analog of (−)-Δ9-tetrahydrocannabinol, binds to brain cannabinoid (CB1) receptors and activates signal transduction pathways. To date, an exact molecular description of the CB1 receptor is not yet available. Utilizing the minor binding pocket of the CB1 receptor as the primary ligand interaction site, we explored HU210 binding using lipid bilayer molecular dynamics (MD) simulations. Among the potential ligand contact residues, we identified residues Phe-1742.61, Phe-1772.64, Leu-1933.29, and Met-3636.55as being critical for HU210 binding by mutational analysis. Using these residues to guide the simulations, we determined essential cannabinoid-binding domains in the CB1 receptor, including the highly sought after hydrophobic pocket important for the binding of the C3 alkyl chain of classical and nonclassical cannabinoids. Analyzing the simulations of the HU210-CB1 receptor complex, the CP55940-CB1 receptor complex, and the (−)-Δ9-tetrahydrocannabinol-CB1 receptor complex, we found that the positioning of the C3 alkyl chain and the aromatic stacking between Trp-3566.48and Trp-2795.43is crucial for the Trp-3566.48rotamer change toward receptor activation through the rigid-body movement of H6. The functional data for the mutant receptors demonstrated reductions in potency for G protein activation similar to the reductions seen in ligand binding affinity for HU210.