Mechanism of partial agonist action at the NR1 subunit of NMDA receptors
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors
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DOI：
10.1016/j.neuron.2005.05.022
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发表时间：
2005-07-07
期刊：
影响因子：
16.2
通讯作者：
Gouaux, E
中科院分区：
文献类型：
--
作者：
Inanobe, A;Furukawa, H;Gouaux, E
部分激动剂产生配体门控离子通道的次极大激活。为了解决NMDA受体NR1亚基上的部分激动剂作用问题，我们对1-氨基环丙烯-1-羧酸（ACPC）、1-氨基环丁烷-1-羧酸（ACBC）和1-氨基环戊烷-1-羧酸（环亮氨酸）这三种碳环逐渐变大的化合物进行了晶体学和电生理研究。尽管ACPC和ACBC分别部分激活了80%和42%的NMDA受体，但它们的NR1配体结合核心的共晶结构显示出与甘氨酸（一种完全激动剂）复合物相同程度的结构域关闭，这表明NR1亚基提供了一种不同于进化相关的GluR2 （ampa敏感受体）的部分激动剂作用的新模式。环亮氨酸起拮抗剂作用，稳定开裂构象。nr1 -环亮氨酸复合物形成与GluR2二聚体相似的二聚体，从而表明AMPA和NMDA受体中存在亚基-亚基相互作用的保守模式。
Partial agonists produce submaximal activation of ligand-gated ion channels. To address the question of partial agonist action at the NR1 subunit of the NMDA receptor, we performed crystallographic and electrophysiological studies with 1-aminocyclopropane-1-carboxylic acid (ACPC), 1-aminocyclobutane-l-carboxylic acid (ACBC), and 1-aminocyclopentane-1-carboxylic acid (cycloleucine), three compounds with incrementally larger carbocyclic rings. Whereas ACPC and ACBC partially activate the NMDA receptor by 80% and 42%, respectively, their cocrystal structures of the NR1 ligand binding core show the same degree of domain closure as found in the complex with glycine, a full agonist, illustrating that the NR1 subunit provides a new paradigm for partial agonist action that is distinct from that of the evolutionarily related GluR2, AMPA-sensitive receptor. Cycloleucine behaves as an antagonist and stabilizes an open-cleft conformation. The NR1-cycloleucine complex forms a dimer that is similar to the GluR2 dimer, thereby suggesting a conserved mode of subunit-subunit interaction in AMPA and NMDA receptors.