Structural insights into binding of therapeutic channel blockers in NMDA receptors.
Structural insights into binding of therapeutic channel blockers in NMDA receptors.
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DOI：
10.1038/s41594-022-00772-0
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发表时间：
2022-06
影响因子：
16.8
通讯作者：
Furukawa, Hiro
中科院分区：
文献类型：
--
作者：
Chou, Tsung-Han;Epstein, Max;Michalski, Kevin;Fine, Eve;Biggin, Philip C.;Furukawa, Hiro
由N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性信号传导对于脑发育和功能以及神经系统疾病和障碍至关重要。NMDAR的通道阻断剂由于其治疗抑郁症、阿尔茨海默病和癫痫的潜力而受到医学关注。然而，由于在跨膜结构域内的结合位点处获得高分辨率结构的挑战，结合和通道阻断的精确机制仍然有限。在这里，我们监测的结合三个临床上重要的通道阻滞剂：苯环利定，氯胺酮，美金刚胺在GluN 1 -2B NMDARs在本地分辨率为2.5至3.5 μ m的结合位点周围使用单粒子电子冷冻显微镜，分子动力学模拟，和电生理学。通道阻滞剂与孔衬残留物形成不同程度的相互作用，其主要控制关闭速度，但不控制打开速度。我们对三种独特的NMDAR通道阻滞剂的比较分析为开发具有最小副作用的治疗化合物提供了蓝图。
Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest due to their potential for treating depression, Alzheimer’s disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited due to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5 to 3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects.
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影响因子：
16.2
作者：
Jespersen A;Tajima N;Fernandez-Cuervo G;Garnier-Amblard EC;Furukawa H
通讯作者：
Furukawa H
影响因子：
5.3
作者：
Blanpied，TA;Clarke，RJ;Johnson，JW
通讯作者：
Johnson，JW
影响因子：
5.3
作者：
Jones, KS;VanDongen, HMA;VanDongen, AMJ
通讯作者：
VanDongen, AMJ
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1085/jgp.201812032
发表时间：
2018-08-06
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hansen KB;Yi F;Perszyk RE;Furukawa H;Wollmuth LP;Gibb AJ;Traynelis SF
通讯作者：
Traynelis SF