Structure of Gαi1 bound to a GDP-selective peptide provides insight into guanine nucleotide exchange
Structure of Gαi1 bound to a GDP-selective peptide provides insight into guanine nucleotide exchange
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DOI：
10.1016/j.str.2005.04.007
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发表时间：
2005-07-01
期刊：
影响因子：
5.7
通讯作者：
Siderovski, DP
中科院分区：
文献类型：
--
作者：
Johnston, CA;Willard, FS;Siderovski, DP
异源三聚体G蛋白是调节细胞生理学中涉及的许多信号通路的分子开关。这一特征是通过采用两个主要状态来实现的：不活跃的GDP绑定状态和活跃的GTP绑定状态。在基础条件下，G蛋白以无活性的GDP结合状态存在;因此，核苷酸交换对信号传导的开始至关重要。尽管我们了解G蛋白信号通路，但核苷酸交换的机制仍然难以捉摸。我们采用噬菌体展示技术来鉴定核苷酸状态依赖性G α结合肽。在此，我们报告了GDP选择性G α结合肽KB-752，其增强G α（i）亚基的自发核苷酸交换。G α（i1）/肽复合物的结构测定揭示了Ga开关区域的独特变化，预测通过创建GDP解离途径来增强核苷酸交换。我们的研究结果投光到一个潜在的机制，G α亚基采用适合核苷酸交换的构象。
Heterotrimeric G proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP bound state and an active, GTP bound state. Under basal conditions, G proteins exist in the inactive, GDP bound state; thus, nucleotide exchange is crucial to the onset of signaling. Despite our understanding of G protein signaling pathways, the mechanism of nucleotide exchange remains elusive. We employed phage display technology to identify nucleotide state-dependent G alpha binding peptides. Herein, we report a GDP-selective G alpha binding peptide, KB-752, that enhances spontaneous nucleotide exchange of G alpha(i) subunits. Structural determination of the G alpha(i1)/peptide complex reveals unique changes in the Ga switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which G alpha subunits adopt a conformation suitable for nucleotide exchange.