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The structural basis of the dominant negative phenotype of the G alpha(i1)beta(1)gamma(2) G203A/A326S heterotrimer

文献类型：期刊论文

作者Liu, Ping3; Jia, Ming-zhu3; Zhou, X. Edward1; De Waal, Parker W.1; Dickson, Bradley M.2; Liu, Bo3; Hou, Li3; Yin, Yan-ting3; Kang, Yan-yong1; Shi, Yi3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2016-09
卷号37期号:9页码:1259-1272
关键词dominant negative G alpha(i1)beta(1)gamma(2) heterotrimer G203A A326S crystal structure GPCR GDP
ISSN号1671-4083
DOI10.1038/aps.2016.69
文献子类Article
英文摘要Aim: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Ga-i1 alpha(1)gamma(2) G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Ga-i1 alpha(1)gamma(2). Methods: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. Results: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Ga-G beta gamma. interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of G alpha(i) and the N-termini of both the G beta and G gamma subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. Conclusion: Overall, the results suggest that the mutations impede guanine nucleotide binding and G alpha-G beta gamma protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations.
WOS关键词PROTEIN ALPHA-SUBUNITS ; CRYSTAL-STRUCTURE ; GTP HYDROLYSIS ; ADENYLYL-CYCLASE ; 2.0 ANGSTROM ; GAMMA-S ; MUTANT ; G(I-ALPHA-1) ; INHIBITION ; COMPLEX
资助项目National Natural Science Foundation of China[31300607] ; Shanghai Science and Technology Committee[13ZR1447600] ; Shanghai Rising-Star Program[14QA1404300] ; Outstanding Young Scientist Foundation, Chinese Academy of Sciences (CAS)[00000000] ; Youth Innovation Promotion Association CAS[00000000] ; SANOFI-SIBS Scholarship[00000000] ; Jay and Betty Van Andel Foundation, Amway (China)[00000000] ; Ministry of Science and Technology of China[2012CB910403] ; Ministry of Science and Technology of China[2013CB910601] ; Ministry of Science and Technology of China[XDB08020303]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000383046000012
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/275911]  
专题药物靶标结构与功能中心
化学蛋白质组学研究中心
通讯作者Xu, H. Eric; Jiang, Yi
作者单位1.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA;
2.Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr, Ctr Struct & Funct Drug Targets,CAS Key Lab Recep, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Liu, Ping,Jia, Ming-zhu,Zhou, X. Edward,et al. The structural basis of the dominant negative phenotype of the G alpha(i1)beta(1)gamma(2) G203A/A326S heterotrimer[J]. ACTA PHARMACOLOGICA SINICA,2016,37(9):1259-1272.
APA Liu, Ping.,Jia, Ming-zhu.,Zhou, X. Edward.,De Waal, Parker W..,Dickson, Bradley M..,...&Jiang, Yi.(2016).The structural basis of the dominant negative phenotype of the G alpha(i1)beta(1)gamma(2) G203A/A326S heterotrimer.ACTA PHARMACOLOGICA SINICA,37(9),1259-1272.
MLA Liu, Ping,et al."The structural basis of the dominant negative phenotype of the G alpha(i1)beta(1)gamma(2) G203A/A326S heterotrimer".ACTA PHARMACOLOGICA SINICA 37.9(2016):1259-1272.

入库方式： OAI收割

来源：上海药物研究所

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