...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interdomain communication revealed in the diabetes drug target mitoNEET
【24h】

Interdomain communication revealed in the diabetes drug target mitoNEET

机译:糖尿病药物靶标mitoNEET中揭示了域间通信

获取原文
获取原文并翻译 | 示例
           

摘要

MitoNEET is a recently identified drug target for a commonly prescribed diabetes drug, Pioglitazone. It belongs to a previously uncharacterized ancient family of proteins for which the hallmark is the presence of a unique 39 amino acid CDGSH domain. In order to characterize the folding landscape of this novel fold, we performed thermodynamic simulations on MitoNEET using a structure-based model. Additionally, we implement a method of contact map clustering to partition out alternate pathways it) folding. This cluster analysis reveals a detour late in folding and enables us to carefully examine the folding mechanism of each pathway rather than the macroscopic average. We observe that tightness in a region distal to the iron-sulfur cluster creates a constraint in folding and additionally appears to mediate communication in folding between the two domains of the protein. We demonstrate that by making changes at this site we are able to tweak the order of folding events in the cluster binding domain as well as decrease the barrier to folding.
机译:MitoNEET是最近确定的常用处方糖尿病药物吡格列酮的药物靶标。它属于一个以前未表征的古老蛋白质家族,其标志是存在一个独特的39个氨基酸的CDGSH结构域。为了表征这种新颖折叠的折叠景观,我们使用基于结构的模型对MitoNEET进行了热力学模拟。此外,我们实现了一种联系地图聚类的方法,以划分出折叠的替代路径。这种聚类分析揭示了折叠后期的弯路,使我们能够仔细检查每个路径的折叠机制,而不是宏观平均值。我们观察到,在铁-硫簇远端的区域中的紧密度在折叠中产生了约束,并且另外似乎在蛋白质的两个结构域之间在折叠中介导了通讯。我们证明,通过在此站点进行更改,我们可以调整簇绑定域中折叠事件的顺序,并减少折叠的障碍。

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