Original Articles
Yuan Zhang, Zhihua Wang, Xiaoyao Ma, Shengnan Yang, Xueyan Hu, Jin Tao, Yuanyuan Hou, Gang Bai. Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 294-303

Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins
Yuan Zhang, Zhihua Wang, Xiaoyao Ma, Shengnan Yang, Xueyan Hu, Jin Tao, Yuanyuan Hou, Gang Bai
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China
Abstract:
Members of the RAS proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of RAS/GTP with RAS guanine nucleotide exchange factors (GEFs), impair RASeffector interactions, and suppress RAS localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on RAS stability. We found that glycyrrhetinic acid may bind to the P-loop of RAS and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in RAS. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.
Key words:    Glycyrrhetinic acid    RAS    Allosteric inhibitor    RAS/MAPK signalling   
Received: 2018-08-07     Revised: 2018-10-25
DOI: 10.1016/j.apsb.2018.11.002
Funds: This work was supported by grants from National Natural Science Foundation of China (Grant Nos.81430095,81673616,and 81473403);and International Cooperation and Exchange of the National Natural Science Foundation of China (Grant No.81761168039).
Corresponding author: Yuanyuan Hou, Gang Bai     Email:houyy@nankai.edu.cn;gangbai@nankai.edu.cn
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Yuan Zhang
Zhihua Wang
Xiaoyao Ma
Shengnan Yang
Xueyan Hu
Jin Tao
Yuanyuan Hou
Gang Bai

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