Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process

作者：Xiong, Yuqing; Zeng, Juan; Xia, Fei^*; Cui, Qiang; Deng, Xianming^*; Xu, Xin^*

来源：Journal of Computational Chemistry, 2022, 43(13): 906-916.

DOI：10.1002/jcc.26846

• binding pockets
• conformations
• Ras complexes
• REMD simulation

The human Son of Sevenless (SOS) activates the signal-transduction protein Ras by forming the complex SOS center dot Ras and accelerating the guanosine triphosphate (GTP) exchange in Ras. Inhibition of SOS center dot Ras could regulate the function of Ras in cells and has emerged as an effective strategy for battling Ras related cancers. A key factor to the success of this approach is to understand the conformational change of Ras during the GTP exchange process. In this study, we perform an extensive molecular dynamics simulation to characterize the specific conformations of Ras without and with guanine nucleotide exchange factors (GEFs) of SOS, especially for the substates of State 1 of HRasGTP center dot Mg2+. The potent binding pockets on the surfaces of the RasGDP center dot Mg2+, the S1.1 and S1.2 substates in State 1 of RasGTP center dot Mg2+ and the ternary complexes with SOS are predicted, including the binding sites of other domains of SOS. These findings help to obtain a more thorough understanding of Ras functions in the GTP cycling process and provide a structural foundation for future drug design.

• 单位
  厦门大学; 广东医学院; 复旦大学