Structural and Dynamical Basis of G Protein Inhibition by YM-254890 and FR900359: An Inhibitor in Action
Structural and Dynamical Basis of G Protein Inhibition by YM-254890 and FR900359: An Inhibitor in Action
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DOI：
10.1021/acs.jcim.9b00433
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Hausch, Felix
中科院分区：
文献类型：
--
作者：
Tietze, Daniel;Kaufmann, Desiree;Hausch, Felix
G蛋白的特异性抑制具有很大的药理学前景，例如靶向致癌的G（q/11）蛋白，并且可以通过两种天然产物FR900359 （FR）和YM-254890 （YM）实现。不幸的是，最近基于理性设计的方法来处理除G（q/11/14）亚型以外的G蛋白并不成功，主要是由于这些新模态化合物的构象复杂性。在这里，我们报告了YM的水衍生核磁共振结构，它与晶体结构中发现的G(q)结合的YM的构象有很大不同。晶体结构的再分析表明，YM的水源核磁共振结构也代表了电子密度的有效解。广泛的分子动力学模拟揭示了与pdb3ah8的原始YM构象相比，水衍生核磁共振结构的结合亲和力要高得多。采用硅设计的快速激活G蛋白构象分子动力学数据最终显示抑制剂如何损害阻碍核苷酸交换所需的G蛋白结构域运动。
Specific inhibition of G proteins holds a great pharmacological promise to, e.g., target oncogenic G(q/11) proteins and can be achieved by the two natural products FR900359 (FR) and YM-254890 (YM). Unfortunately, recent rational-design-based approaches to address G proteins other than G(q/11/14) subtypes were not successful mainly due to the conformational complexity of these new modalities-like compounds. Here, we report the water-derived NMR structure of YM, which strongly differs from the conformation of G(q)-bound YM as found in the crystal structure. Reanalysis of the crystal structure suggests that the water-derived NMR structure of YM also represents a valid solution of the electron density. Extensive molecular dynamic simulations unveiled much higher binding affinities of the water-derived NMR structure compared to the original YM conformation of pdb 3ah8. Employing a in-silico-designed, fast activating G protein conformation molecular dynamics data ultimately show how the inhibitor impairs the domain motion of the G protein necessary to hinder nucleotide exchange.