Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints
Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints
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DOI：
10.1016/j.str.2015.09.012
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发表时间：
2015-12-01
期刊：
影响因子：
5.7
通讯作者：
Guallar, Victor
中科院分区：
文献类型：
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作者：
Edman, Karl;Hosseini, Ali;Guallar, Victor
类固醇受体药物已经问世半个多世纪了，但配体结合机制的细节仍然难以捉摸。我们解析了糖皮质激素和盐皮质激素受体的 X 射线结构，以鉴定螺旋 6-7 区域的保守可塑性，该区域将配体结合袋延伸至受体表面。由于没有内源配体利用该区域，我们假设它构成了结合事件的一个组成部分。广泛的全原子无偏配体出口和入口模拟证实了配体结合途径，该途径使观察到的结构可塑性发挥了关键的功能作用。动力学测量表明，受体停留时间与结构和模拟中观察到的结构重排相关。最终，我们的研究结果揭示了为什么大自然保留了打开该区域的能力，并强调了配体进入过程细节的差异如何导致类固醇受体的不同进化限制。
Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors.