Molecular switch in signal transduction: Reaction paths of the conformational changes in ras p21
Molecular switch in signal transduction: Reaction paths of the conformational changes in ras p21
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DOI：
10.1073/pnas.94.22.11905
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发表时间：
1997-10-28
影响因子：
11.1
通讯作者：
Karplus, M
中科院分区：
文献类型：
--
作者：
Ma, JP;Karplus, M
GTP水解引发的ras p21构象变化在信号转导途径中起着至关重要的作用，构象变化的路径是通过分子动力学模拟确定的，完整约束引导系统从已知的GTP结合结构（除去γ-磷酸）到GDP结合结构，模拟是用围绕蛋白质的水分子壳完成的，在开关I区域，经历较大位移的Tyr-32侧链在空间中移动因此，在同源 RafRBD-Raps 复合物中与 Raf 相互作用的带电残基 Glu-31 和 Asp-33 在转变过程中保持暴露，在开关 II 区域中，α 2 和环 4 的构象变化强烈耦合，在开关 II 区域中的 Arg-68 和 Tyr-71 与 Glu-37 之间形成瞬时氢键复合物。开关 I 区域稳定 α 2 的中间构象，并促进 α 2 螺旋转角（残基 66-69）的解开，这反过来又允许环 4 进行更大规模的运动。发现蛋白质和溶剂分子之间的氢键交换在转变中很重要。讨论了结果的可能功能含义。
Conformational changes in ras p21 triggered by the hydrolysis of GTP play an essential role in the signal transduction pathway, The path for the conformational change is determined by molecular dynamics simulation with a holonomic constraint directing the system from the known GTP-bound structure (with the gamma-phosphate removed) to the GDP-bound structure, The simulation is done with a shell of water molecules surrounding the protein, In the switch I region, the side chain of Tyr-32, which undergoes a large displacement, moves through the space between loop 2 and the rest of the protein, rather than on the outside of the protein, As a result, the charged residues Glu-31 and Asp-33, which interact with Raf in the homologous RafRBD-Raps complex, remain exposed during the transition, In the switch II region, the conformational changes of alpha 2 and loop 4 are strongly coupled, A transient hydrogen bonding complex between Arg-68 and Tyr-71 in the switch II region and Glu-37 in switch I region stabilizes the intermediate conformation of alpha 2 and facilitates the unwinding of a helical turn of alpha 2 (residues 66-69), which in turn permits the larger scale motion of loop 4, Hydrogen bond exchange between the protein and solvent molecules is found to be important in the transition, Possible functional implications of the results are discussed.