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首页> 外文期刊>The FEBS journal >Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2
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Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2

机译：负变性调节剂和竞争性拮抗剂的结合可以在离子型谷氨酸受体Glua2处同时发生

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摘要

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 angstrom resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. Database The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code . The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact).
机译：离子型谷氨酸受体是调节中枢神经系统神经传递的配体门控离子通道。AMPA型受体GluA2已知三种主要类型的拮抗剂：用于治疗癫痫的竞争性、非竞争性（即负变构调节剂；NAMs）和非竞争性拮抗剂。我们在此报告了GluA2的4.65埃分辨率X射线结构，揭示了竞争性拮抗剂ZK200775的四个分子和NAM GYKI53655的四个分子能够同时结合。使用负染色电子显微镜，我们显示GYKI53655单独或ZK200775/GYKI53655组合主要导致致密受体形式。激动剂AMPA提供了紧凑和凸起形状的GluA2混合群体，不受GYKI53655添加的影响。综上所述，这表明导致通道闭合的两种不同的拮抗机制是独立的，并且凸起受体和紧密受体之间的分布主要取决于谷氨酸结合位点上结合的配体。数据库晶体结构测定得到的原子坐标和结构因子已以登录代码保存在蛋白质数据库中。电子显微镜三维重建体积已存储在EMDB中（EMD-4875:Apo；EMD-4920:ZK200775/GYKI53655；EMD-4921:AMPA compact；EMD-4922:AMPA/GYKI53655 bulgy；EMD-4923:GYKI53655；EMD-4924:AMPA bulgy；EMD-4925:AMPA/GYKI53655 compact）。

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