Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule
Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule
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DOI：
10.1073/pnas.1003553107
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发表时间：
2010-08-03
影响因子：
11.1
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Nishimura, Akiyuki;Kitano, Ken;Itoh, Hiroshi
异源三聚体GTP结合蛋白（G蛋白）将G蛋白偶联受体（GPCR）感知的细胞外刺激传递到细胞内信号级联。人类中存在数百种GPCR，并且是当今使用的大部分药物的靶点。由于G蛋白受GPCR调控，因此直接调节G蛋白的小分子具有成为治疗剂的潜力。然而，开发调节剂的策略受到缺乏特异性调节剂结合的靶向位点的结构知识的阻碍。在这里，我们提出的环缩酚酸肽YM-254890，这是最近发现的G（q）-选择性抑制剂的作用机制。YM-254890通过抑制G α（q）释放GDP，特异性抑制G（q）蛋白α亚基（G α（q））的GDP/GTP交换反应。G α（q）β γ-YM-254890复合物的X射线晶体结构分析显示，YM-254890结合连接G α（q）的GT β和螺旋结构域的两个结构域间接头之间的疏水裂缝。该结合通过与开关I的直接相互作用来稳定非活性GDP结合形式，并损害接头柔性。我们的研究为开发选择性抑制每个G α亚基的小分子提供了一个新的靶向位点，并深入了解G蛋白活化的分子机制。
Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G(q)-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of alpha subunit of G(q) protein (G alpha(q)) by inhibiting the GDP release from G alpha(q). X-ray crystal structure analysis of the G alpha(q)beta gamma-YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the G alpha(q). The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each G alpha subunit and an insight into the molecular mechanism of G protein activation.