Interdomain communication revealed in the diabetes drug target mitoNEET
Interdomain communication revealed in the diabetes drug target mitoNEET
复制标题
DOI：
10.1073/pnas.1017604108
复制
发表时间：
2011-03-29
影响因子：
11.1
通讯作者：
Onuchic, Jose N.
中科院分区：
文献类型：
--
作者：
Baxter, Elizabeth L.;Jennings, Patricia A.;Onuchic, Jose N.
MitoNEET是最近确定的常用糖尿病药物吡格列酮的药物靶点。它属于以前未表征的古老蛋白质家族，其标志是存在独特的39个氨基酸CDGSH结构域。为了表征这种新型折叠的折叠景观，我们使用基于结构的模型对MitoNEET进行了热力学模拟。此外，我们实现了一种接触图聚类的方法来划分出折叠的替代途径。这种聚类分析揭示了一个迂回后期折叠，使我们能够仔细研究折叠机制的每一个途径，而不是宏观平均。我们观察到，铁硫簇远端区域的紧密性在折叠中产生了约束，并且似乎还介导了蛋白质两个结构域之间的折叠通信。我们证明，通过在这个网站上的变化，我们能够调整的顺序，折叠事件的簇结合域，以及减少折叠的障碍。
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 in 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.