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Internal water channel formation in CXCR4 is crucial for G i -protein coupling upon activation by CXCL12
Communications Chemistry ( IF 5.9 ) Pub Date : 2020-10-08 , DOI: 10.1038/s42004-020-00383-0
Chun-Chun Chang , Je-Wen Liou , Kingsley Theras Primus Dass , Ya-Tzu Li , Shinn-Jong Jiang , Sheng-Feng Pan , Yu-Chen Yeh , Hao-Jen Hsu

Chemokine receptor CXCR4 is a major drug target for numerous diseases because of its involvement in the regulation of cell migration and the developmental process. In this study, atomic-level molecular dynamics simulations were used to determine the activation mechanism and internal water formation of CXCR4 in complex with chemokine CXCL12 and Gi-protein. The results indicated that CXCL12-bound CXCR4 underwent transmembrane 6 (TM6) outward movement and a decrease in tyrosine toggle switch by eliciting the breakage of hydrophobic layer to form a continuous internal water channel. In the GDP-bound Gαi-protein state, the rotation and translation of the α5-helix of Gαi-protein toward the cytoplasmic pocket of CXCR4 induced an increase in interdomain distance for GDP leaving. Finally, an internal water channel formation model was proposed based on our simulations for CXCL12-bound CXCR4 in complex with Gαi-protein upon activation for downstream signaling. This model could be useful in anticancer drug development.



中文翻译:

CXCR4 内部水通道的形成对于 CXCL12 激活后的 G i 蛋白偶联至关重要

趋化因子受体 CXCR4 是许多疾病的主要药物靶标,因为它参与细胞迁移和发育过程的调节。在这项研究中,使用原子级分子动力学模拟来确定 CXCR4 与趋化因子 CXCL12 和 G i蛋白复合物的激活机制和内部水形成。结果表明,CXCL12 结合的 CXCR4 经历跨膜 6 (TM6) 向外运动和酪氨酸拨动开关的减少,通过引起疏水层的破裂形成连续的内部水通道。在 GDP 结合的 G αi蛋白状态下,G αi的 α5-螺旋的旋转和平移- 蛋白质朝向 CXCR4 的细胞质口袋诱导 GDP 离开的域间距离增加。最后,基于我们对与 G αi蛋白复合的 CXCL12 结合 CXCR4 的模拟,提出了一个内部水通道形成模型,用于激活下游信号。该模型可用于抗癌药物开发。

更新日期:2020-10-08
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