Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins

作     者：Yuan Zhang Zhihua Wang Xiaoyao Ma Shengnan Yang Xueyan Hu Jin Tao Yuanyuan Houn Gang Bai 

作者机构：State Key Laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai University 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第2期

页      面：294-303页

核心收录：

学科分类：1008[医学-中药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by grants from National Natural Science Foundation of China (Grant Nos. 81430095, 81673616, and 81473403) International Cooperation and Exchange of the National Natural Science Foundation of China (Grant No. 81761168039) 

主　　题：Glycyrrhetinic acid RAS Allosteric inhibitor RAS/MAPK signalling 

摘      要：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.