Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2,The FEBS Journal

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Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-06-15 , DOI: 10.1111/febs.15455
Christian Krintel ₁ , Jerzy Dorosz ₁ , Andreas Haahr Larsen ₂ , Thor Seneca Thorsen ₁ , Raminta Venskutonytė _{1,

3} , Osman Mirza ₁ , Michael Gajhede ₁ , Thomas Boesen ₄ , Jette Sandholm Kastrup ₁

Affiliation

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 Å 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.

中文翻译：

负变构调节剂和竞争性拮抗剂的结合可在离子型谷氨酸受体GluA2上同时发生

离子型谷氨酸受体是控制中枢神经系统中神经传递的配体门控离子通道。AMPA型受体GluA2已知三种主要的拮抗剂：竞争性，非竞争性（即负变构调节剂；NAM），用于治疗癫痫和非竞争性拮抗剂。我们在这里报告了GluA2的4.65Å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，我们显示单独的GYKI53655或组合的ZK200775 / GYKI53655主要产生紧密的受体形式。激动剂AMPA可提供不受GYKI53655添加影响的GluA2紧凑型和凸起形状的混合群体。综上所述，这表明导致通道关闭的两种不同的拮抗作用机制是独立的，并且膨大和紧密受体之间的分布主要取决于结合在谷氨酸结合位点上的配体。

更新日期：2020-06-15

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