...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Structural consequences of D481N/K483Q mutation at glycine binding site of NMDA ionotropic glutamate receptors: a molecular dynamics study.
【24h】

Structural consequences of D481N/K483Q mutation at glycine binding site of NMDA ionotropic glutamate receptors: a molecular dynamics study.

机译：D481N / K483Q突变在NMDA离子型谷氨酸受体的甘氨酸结合位点的结构后果：分子动力学研究。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

N-Methyl-D-Aspartate (NMDA) receptors are the ligand gated as well as voltage sensitive ionotropic glutamate receptors, widely distributed in the vertebrate central nervous system and they play critical role in the pathogenesis of schizophrenia. Molecular dynamics simulations have been carried out on high resolution crystal structure of NR1 subunit of NMDA receptor ligand binding core (S1S2) in four different conformations. We have investigated consequence of D481N/K483Q double mutation of NR1 subunit from simulation results of (a) glycine bound form (WG), (b) unbound (closed-apo) form (WOG), (c) a double mutated form (DM), and (d) the antagonist (5,7-dichlorokynuric acid) bound form (DCKA). The MD simulations and simulated annealing for 4ns show a distinct conformation for the double mutated conformation that neither follows the antagonist nor apo conformation. There are two distinct sites, loop1 and loop2 where the double mutated structure in its glycine bound form shows significant RMSD deviations as compared to the wild-type. The interactions of glycine with the receptor remain theoretically unchanged in the double mutated structure and there is no detachment of S1S2 domains. The results suggest that separation of S1 and S2 domains may not be essential for channel inactivation. Therefore, it is hypothesized that hypoactivation of NMDA receptor channels may arise out of the conformational changes at non-conserved Loop1 and Loop2 regions observed in the mutated structure. The Loop1 and Loop2 regions responsible for inter-subunit interactions in a functional NMDA receptor, may therefore, render the ligand bound form defunct. This may account for behavioral anomalies due to receptor inactivation seen in grin1 mutated mice.
机译：N-甲基-D-天门冬氨酸（NMDA）受体是门控的配体以及电压敏感的离子型谷氨酸受体，广泛分布在脊椎动物中枢神经系统中，它们在精神分裂症的发病机理中起关键作用。对NMDA受体配体结合核心（S1S2）的NR1亚基的高分辨率晶体结构以四种不同构型进行了分子动力学模拟。我们已经从（a）甘氨酸结合形式（WG），（b）未结合（封闭apo）形式（WOG），（c）双重突变形式（DM）的模拟结果中研究了NR1亚基的D481N / K483Q双重突变的结果），以及（d）拮抗剂（5,7-二氯kynuric acid）结合形式（DCKA）。 MD模拟和4ns的模拟退火显示了既不遵循拮抗剂也不没有载脂蛋白构象的双突变构象的独特构象。有两个不同的位点，loop1和loop2，与野生型相比，其甘氨酸结合形式的双突变结构显示出显着的RMSD偏差。甘氨酸与受体的相互作用在双突变结构中理论上保持不变，并且没有S1S2结构域的分离。结果表明，S1和S2域的分离对于通道失活可能不是必需的。因此，假设在突变结构中观察到的非保守Loop1和Loop2区域的构象变化可能引起NMDA受体通道的过度活化。因此，负责功能性NMDA受体中亚基间相互作用的Loop1和Loop2区可能使配体结合形式失效。这可能是由于grin1突变小鼠中受体失活导致的行为异常的原因。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号