Crystal structure of a human GABAA receptor.
Crystal structure of a human GABAA receptor.
复制标题
人类 GABAA 受体的晶体结构。
DOI：
10.1038/nature13293
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发表时间：
2014-08-21
期刊：
影响因子：
64.8
通讯作者：
Aricescu AR
中科院分区：
文献类型：
--
作者：
Miller PS;Aricescu AR
A型γ-氨基丁酸受体（GABAARs）是人脑中快速抑制性突触传递的主要介质。GABAAR信号的下降会引发过度活跃的神经系统疾病，如失眠，焦虑和癫痫。在这里，我们提出了第一个三维结构的GABAAR，人类β3 homopentamer，在3 μ m的分辨率。这种结构揭示了真核Cys环受体独特的结构元件，解释了多种人类疾病突变的机制后果，并显示了保守的N-连接聚糖的惊人结构作用。该受体被结晶结合到一个以前未知的激动剂，苄脒，开辟了一个新的途径，合理设计的GABAAR调节剂。沟道区在孔的底部形成闭合的栅极，代表减敏状态。这些结果为五聚体配体门控离子通道的信号转导机制提供了新的见解，并增强了目前对GABA能神经传递的理解。
Type-A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human β3 homopentamer, at 3 Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows a surprising structural role for a conserved N-linked glycan. The receptor was crystallised bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitised state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.