Two distinct conformers of SAG investigated by solution NMR and variable-temperature experiments
Two distinct conformers of SAG investigated by solution NMR and variable-temperature experiments
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通过溶液核磁共振和变温实验研究了 SAG 的两种不同构象
DOI：
10.1016/j.jpba.2018.12.019
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发表时间：
2019
影响因子：
3.4
通讯作者：
Cui Xiaoliang
中科院分区：
文献类型：
--
作者：
Jiang Haipeng;Wang Xian;Cui Xiaoliang
SAG （Smo agonist）是Smo受体的高特异性激动剂，被广泛用作化学探针来探索激活hh信号通路的治疗价值。本文通过溶液核磁共振揭示了两种不同构象（A和B）的共存，并用ROESY光谱和MMFF94程序分析了两种构象的三维结构差异。发现两种构象都是Smo受体的激动剂，D2O溶液中的次构象（构象B）通过分子对接对Smo受体具有更高的亲和力。结果揭示了两种不同的SAG构象参与Smo受体激活的细节，也为设计更有效的Smo受体激动剂提供了参考。利用变温核磁共振实验研究了两种构象的交换动力学，结果表明，两种构象的比例与溶剂有明显的依赖关系，因此，在将SAG作为化学探针时，月经类型是影响其生物活性的另一个重要因素。
SAG (Smo agonist) is high specific agonist of Smo receptor, it is widely used as chemical probe to explore the therapeutic value of activating the Hh-signaling pathway. In the present work, the coexistence of two distinct conformers (A and B) of SAG are revealed by solution NMR, the 3D structural difference of the two conformers are elucidated by ROESY spectroscopy and MMFF94 program. It is discovered that both conformers are agonists of Smo receptor, and the minor conformer (conformer B) in D2O solution has higher affinity to Smo receptor by molecular docking. The result showed the detail about two distinct conformers of SAG are involved in activation of Smo receptor, and also provides information for designing more effective agonist of Smo by mimicking B conformer of SAG. By exchange dynamics investigation using variable-temperature NMR experiments, the ratio of two conformers has been shown to be drastically solvent dependent, so, the menstruum type is another important influence factor of SAG bioactivity, when using SAG as chemical probe.