Zeng J, Treutlein H R, Simonson T
Laboratoire de Biologie Structurale (CNRS), IGBMC Illkirch (C.U. de Strasbourg), France.
Proteins. 1999 Apr 1;35(1):89-100.
The protein Raf is an immediate downstream target of Ras in the MAP kinase signalling pathway. The complex of Ras with the Ras-binding domain (RBD) of Raf has been modelled by homology to the (E30D,K31E)-Rap1A:RBD complex, and both have been subjected to multiple molecular dynamics simulations in solution. While both complexes are stable, several rearrangements occur in the Ras:RBD simulations: the RBD loop 100-109 moves closer to Ras, Arg73 in the RBD moves towards Ras to form a salt bridge with Ras-Asp33, and Loop 4 of the Ras switch II region shifts upwards toward the RBD. The Ras:RBD interactions (including the RBD-Arg73 interaction) are consistent with available NMR and mutagenesis data on the Ras: RBD complex in solution. The Ras switch II region does not interact directly with the RBD, although indirect interactions exist through the effector domain and bridging water molecules. No large-scale RBD motion is seen in the Ras:RBD complex, compared to the Rap:RBD complex, to suggest an allosteric activation of Raf by Ras. This may be because the Raf kinase domain (whose structure is unknown) is not included in the model.
蛋白质Raf是丝裂原活化蛋白激酶（MAP）信号通路中Ras的直接下游靶点。Ras与Raf的Ras结合结构域（RBD）形成的复合物已通过与（E30D，K31E）-Rap1A:RBD复合物的同源性进行建模，并且两者都在溶液中进行了多次分子动力学模拟。虽然两个复合物都是稳定的，但在Ras:RBD模拟中发生了一些重排：RBD的环100-109向Ras靠近，RBD中的Arg73向Ras移动以与Ras-Asp33形成盐桥，并且Ras开关II区域的环4向上向RBD移动。Ras:RBD相互作用（包括RBD-Arg73相互作用）与溶液中Ras:RBD复合物的现有核磁共振（NMR）和诱变数据一致。Ras开关II区域不直接与RBD相互作用，尽管通过效应器结构域和桥连水分子存在间接相互作用。与Rap:RBD复合物相比，在Ras:RBD复合物中未观察到RBD的大规模运动，这表明Ras对Raf没有别构激活作用。这可能是因为模型中未包含Raf激酶结构域（其结构未知）。
