Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process. Issue 13 (24th March 2022)

• Record Type: Journal Article
• Authors: Xiong, Yuqing; Zeng, Juan; Xia, Fei; Cui, Qiang; Deng, Xianming; Xu, Xin
• Is Part Of: Journal of computational chemistry. Volume 43:Issue 13(2022)
• Page Start: 906
• Page End: 916
• Publication Date: 2022-03-24
• Subjects: binding pockets -- conformations -- Ras complexes -- REMD simulation; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.26846
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract: The human Son of Sevenless (SOS) activates the signal‐transduction protein Ras by forming the complex SOS·Ras and accelerating the guanosine triphosphate (GTP) exchange in Ras. Inhibition of SOS·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∙Mg 2+ . The potent binding pockets on the surfaces of the RasGDP∙Mg 2+, the S1.1 and S1.2 substates in State 1 of RasGTP∙Mg 2+ 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. Abstract : The catalytic HRas, the allosteric HRAS and the SOS domains in the Ras complexes possess a number of binding pockets of P1, P4, S1 and R1 for small molecules.