X-ray structure of the mammalian GIRK2-βγ G-protein complex.
X-ray structure of the mammalian GIRK2-βγ G-protein complex.
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DOI：
10.1038/nature12241
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发表时间：
2013-06-13
期刊：
影响因子：
64.8
通讯作者：
MacKinnon R
中科院分区：
文献类型：
--
作者：
Whorton MR;MacKinnon R
G 蛋白门控内向整流 K+ (GIRK) 通道允许神经递质通过 G 蛋白偶联受体刺激来控制细胞电兴奋性。在心脏和神经元细胞中，这种控制调节心率和神经回路活动。我们展示了哺乳动物 GIRK2 通道与 βγ G 蛋白亚基复合物的 3.5 Å 分辨率晶体结构，βγ G 蛋白亚基是连接 G 蛋白偶联受体刺激与 K+ 通道活性的中央信号复合物。短程原子和长程静电相互作用使四个 βγ G 蛋白亚基稳定在四个 K+ 通道亚基之间的界面处，从而诱导通道处于预开放状态。预开放状态表现出介于封闭构象和组成性活性突变体开放构象之间的构象。由此产生的结构图与 G 蛋白对 GIRK 通道的“膜界定”激活以及通道门控的特征爆发动力学相一致。这些结构还可以从概念上理解信号脂质 PIP2 和细胞内 Na+ 离子如何参与 GIRK 通道的多配体调节。
G protein-gated inward rectifier K+ (GIRK) channels allow neurotransmitters, via G protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity. We present the 3.5 Å resolution crystal structure of the mammalian GIRK2 channel in complex with βγ G protein subunits, the central signaling complex that links G protein-coupled receptor stimulation to K+ channel activity. Short-range atomic and long-range electrostatic interactions stabilize four βγ G protein subunits at the interfaces between four K+ channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed and constitutively active mutant, open conformations. The resultant structural picture is compatible with “membrane delimited” activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signaling lipid PIP2 and intracellular Na+ ions participate in multi-ligand regulation of GIRK channels.