Structural mechanism of ligand activation in human GABA(B) receptor.
Structural mechanism of ligand activation in human GABA(B) receptor.
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人GABAB受体是对脑中的抑制性神经传递起中枢作用的G蛋白偶联受体。它作为GBR 1和GBR 2亚基的专性异源二聚体发挥作用。在这里，我们提出了第一个晶体结构的GBR 1和GBR 2的胞外结构域之间的异二聚体复合物的载脂蛋白，激动剂结合，拮抗剂结合的形式。载脂蛋白和拮抗剂结合结构代表受体的静息状态;激动剂结合复合物对应于活性状态。这两个亚基在静止时都采取开放构象，并且只有GBR 1在激动剂诱导的受体活化后关闭。激动剂和拮抗剂通过一组重叠的残基锚定在GBR 1的结构域间缝隙中。拮抗剂将GBR 1限制在非活性状态的开放构象，而激动剂诱导其结构域闭合以进行激活。我们的数据揭示了一个独特的激活机制GABAB受体，涉及形成一个新的异源二聚体之间的亚基界面。
Human GABAB receptor is a G-protein coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of GBR1 and GBR2 subunits. Here we present the first crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound, and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes upon agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, while an agonist induces its domain closure for activation. Our data reveals a unique activation mechanism for GABAB receptor that involves the formation of a novel heterodimer interface between subunits.