Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5266-71. doi: 10.1073/pnas.1017604108. Epub 2011 Mar 14.
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.
MitoNEET 是一种最近被确定的药物靶点，针对的是一种常用的糖尿病药物吡格列酮。它属于一个以前未被描述的古老蛋白质家族，其特点是存在一个独特的 39 个氨基酸的 CDGSH 结构域。为了描述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，我们还实施了一种接触图聚类方法，以划分折叠过程中的替代途径。这种聚类分析揭示了折叠过程中的一个迂回，并使我们能够仔细检查每条途径的折叠机制，而不是宏观平均。我们观察到，远离铁硫簇的区域的紧密性会在折叠过程中产生约束，并且似乎还会介导蛋白质两个结构域之间的折叠过程中的信息传递。我们证明，通过在该位点进行改变，我们能够调整簇结合域中折叠事件的顺序，并降低折叠的障碍。
