Department of Pharmacology, Columbia University, New York, New York 10032, USA.
1] Department of Pharmacology, Columbia University, New York, New York 10032, USA [2] Department of Pathology & Cell Biology, Columbia University, New York, New York 10032, USA.
Nature. 2013 Dec 12;504(7479):254-9. doi: 10.1038/nature12725. Epub 2013 Dec 4.
Human GABA(B) (γ-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the 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 on 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, whereas an agonist induces its domain closure for activation. Our data reveal a unique activation mechanism for GABA(B) receptor that involves the formation of a novel heterodimer interface between subunits.
人类 GABA(B)（γ-氨基丁酸 B 型）受体是一种 G 蛋白偶联受体，是大脑中抑制性神经递质传递的核心。它作为亚基 GBR1 和 GBR2 的必需异二聚体发挥作用。在这里，我们展示了 GBR1 和 GBR2 的细胞外结构域之间的异二聚体复合物在apo、激动剂结合和拮抗剂结合形式下的晶体结构。apo 和拮抗剂结合结构代表受体的静止状态；激动剂结合复合物对应于活性状态。在休息时，两个亚基都采用开放构象，只有 GBR1 在受体激活时关闭。激动剂和拮抗剂通过一组重叠的残基锚定在 GBR1 的结构域裂缝中。拮抗剂将 GBR1 限制在无活性状态的开放构象中，而激动剂诱导其结构域关闭以实现激活。我们的数据揭示了 GABA(B)受体的独特激活机制，涉及亚基之间形成新的异二聚体界面。
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