Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors
Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors
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DOI：
10.1038/s41467-019-08291-1
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发表时间：
2019-01-18
影响因子：
16.6
通讯作者：
Furukawa, Hiro
中科院分区：
文献类型：
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作者：
Regan, Michael C.;Zhu, Zongjian;Furukawa, Hiro
对N-甲基-D-天冬氨酸(NMDA)受体的上下文依赖性抑制对于治疗与神经元放电和信号改变相关的神经系统疾病具有重要的治疗意义。这在中风中尤其如此，受影响区域的质子浓度可以增加一个数量级。一类变构抑制剂93系列在如此低的pH环境中对GluN1-GluN2B NMDA受体显示出更强的效力，允许仅在缺血区进行靶向治疗。在这里，我们绘制了GluN1-GluN2B NMDA受体氨基末端结构域的93系列化合物结合部位，并表明N-烷基与结合部位的疏水笼子的相互作用对于pH依赖的抑制是关键的。疏水笼子中残基的突变改变了pH依赖的效力，特别是可以将抑制剂转化为增效剂。我们的研究为开发治疗神经系统疾病的高度特异性神经保护化合物提供了基础。
Context-dependent inhibition of N-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases.