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标题：Gsα-selective G protein antagonists
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作者：M. Hohenegger ; M. Waldhoer ; W. Beindl 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：1
页码：346-351
DOI：10.1073/pnas.95.1.346
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Suramin acts as a G protein inhibitor because it inhibits the rate-limiting step in activation of the G subunit, i.e., the exchange of GDP for GTP. Here, we have searched for analogues that are selective for Gs. Two compounds have been identified: NF449 (4,4',4",4'"-[carbonyl-bis[imino-5,1,3-benzenetriyl bis-(carbonylimino)]]tetrakis-(benzene-1,3-disulfonate) and NF503 (4,4'-[carbonylbis[imino-3,1-phenylene-(2,5-benzimidazolylene)carbonylimino]]bis-benzenesulfonate). These compounds (i) suppress the association rate of guanosine 5'-[{gamma}-thio]triphosphate ([35S]GTP[{gamma}S]) binding to Gs-s but not to Gi-1, (ii) inhibit stimulation of adenylyl cyclase activity in S49 cyc- membranes (deficient in endogenous Gs) by exogenously added Gs-s, and (iii) block the coupling of {beta}-adrenergic receptors to Gs with half-maximum effects in the low micromolar range. In contrast to suramin, which is not selective, NF503 and NF449 disrupt the interaction of the A1-adenosine receptor with its cognate G proteins (Gi/Go) at concentrations that are >30-fold higher than those required for uncoupling of {beta}-adrenergic receptor/Gs tandems; similarly, the angiotensin II type-1 receptor (a prototypical Gq-coupled receptor) is barely affected by the compounds. Thus, NF503 and NF449 fulfill essential criteria for Gs-selective antagonists. The observations demonstrate the feasibility of subtype-selective G protein inhibition.