α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors produce postsynaptic current by transmitting an agonist-induced structural change in the ligand-binding domain (LBD) to the transmembrane channel. Receptors carrying T686S/A substitutions in their LBDs produce weaker glutamate-evoked currents than wild-type (WT) receptors. However, the substitutions induce little differences in the crystal structures of their LBDs. To understand the structural mechanism underlying reduced activities of these AMPAR variants, we analyzed the structural dynamics of WT, T686S, and T686A variants of LBD using nuclear magnetic resonance. The HD exchange studies of the LBDs showed that the kinetic step where the ligand-binding cleft closes was changed by the substitutions, and the substitution-induced population shift from cleft-closed to cleft-open structures is responsible for the reduced activities of the variants. The chemical shift analyses revealed another structural equilibrium between cleft-locked and cleft-partially-open conformations. The substitution-induced population shift in this equilibrium may be related to slower desensitization observed for these variants.

中文翻译：

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由其配体结合域中的取代诱导的AMPA型谷氨酸受体的活性变化的基础机制。

α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体通过将激动剂诱导的配体结合域（LBD）的结构变化传递至跨膜通道来产生突触后电流。与野生型（WT）受体相比，在其LBD中带有T686S / A取代的受体产生的谷氨酸诱发的电流更弱。但是，这些取代几乎不引起其LBD晶体结构的差异。为了了解这些AMPAR变体活性降低的基础机制，我们使用核磁共振分析了LBD的WT，T686S和T686A变体的结构动力学。对LBD的HD交换研究表明，取代键改变了配体结合裂隙闭合的动力学步骤，替代诱导的种群从c裂结构转变为c裂结构是导致变体活性降低的原因。化学位移分析揭示了在left裂锁定和c裂部分打开构象之间的另一种结构平衡。在这种平衡中由取代引起的种群转移可能与这些变体观察到的减敏作用减慢有关。