Molecular lock regulates binding of glycine to a primitive NMDA receptor.
Molecular lock regulates binding of glycine to a primitive NMDA receptor.
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分子锁调节甘氨酸与原始 NMDA 受体的结合。
DOI：
10.1073/pnas.1607010113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Lau,AlbertY
中科院分区：
文献类型：
--
作者：
Yu,Alvin;Alberstein,Robert;Thomas,Alecia;Zimmet,Austin;Grey,Richard;Mayer,MarkL;Lau,AlbertY
人类最早的后生动物祖先包括栉水母Mnemiopsis leidyi。这种栉水母的基因组编码脊椎动物离子型谷氨酸受体 (iGluR) 的同源物，这些受体与甘氨酸激活的 NMDA 受体关系较远，并且以异常高的亲和力与甘氨酸结合。使用配体结合域（LBD）突变体进行电生理学分析，我们证明扰动栉水母特异性域间Arg-Glu盐桥（脊椎动物AMPA、红藻氨酸和NMDA iGluRs中明显不存在）可大大提高脱敏恢复率，而生化分析显示对甘氨酸的亲和力大幅下降。 X射线晶体学分析详细说明了突变引起的结合口袋中的重排，分子动力学模拟表明，域间盐桥充当调节配体结合的空间屏障，并且进入甘氨酸结合的LBD中的开放构象所需的自由能在很大程度上是造成LBD变体之间配体亲和力差异的主要原因。
The earliest metazoan ancestors of humans include the ctenophoreMnemiopsis leidyi. The genome of this comb jelly encodes homologs of vertebrate ionotropic glutamate receptors (iGluRs) that are distantly related to glycine-activated NMDA receptors and that bind glycine with unusually high affinity. Using ligand-binding domain (LBD) mutants for electrophysiological analysis, we demonstrate that perturbing a ctenophore-specific interdomain Arg-Glu salt bridge that is notably absent from vertebrate AMPA, kainate, and NMDA iGluRs greatly increases the rate of recovery from desensitization, while biochemical analysis reveals a large decrease in affinity for glycine. X-ray crystallographic analysis details rearrangements in the binding pocket stemming from the mutations, and molecular dynamics simulations suggest that the interdomain salt bridge acts as a steric barrier regulating ligand binding and that the free energy required to access open conformations in the glycine-bound LBD is largely responsible for differences in ligand affinity among the LBD variants.