Strand swapping regulates the iron-sulfur cluster in the diabetes drug target mitoNEET
Strand swapping regulates the iron-sulfur cluster in the diabetes drug target mitoNEET
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DOI：
10.1073/pnas.1116369109
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发表时间：
2012-02-07
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 Leigh;Jennings, Patricia A.;Onuchic, Jose N.
MitoNEET是最近确定的糖尿病药物靶标，其协调可转移的2Fe-2S簇，并且另外包含不寻常的链交换。在这篇手稿中，我们使用一个双盆结构为基础的模型来预测和描述的折叠和功能的链交换在mitoNEET。我们表明，链未交换的构象是动力学上可访问的，并采用多级控制来调节系统的构象动力学。环境因素，如温度，可以改变路线偏好向非交换途径。此外，我们看到，最近确定的一个区域作为一个调节铰链环，调节构象平衡的折叠挫折。有趣的是，链解交换将应变特异性地转移到簇协调残基，打开簇协调口袋。加强集群协调口袋内的接触打开了一个新的途径之间的交换和未交换的构象，利用裂解绕过展开的盆地。这些结果表明，不同区域内的局部控制影响在调节mitoNEET的2Fe-2S簇中重要的运动。
MitoNEET is a recently identified diabetes drug target that coordinates a transferable 2Fe-2S cluster, and additionally contains an unusual strand swap. In this manuscript, we use a dual basin structure-based model to predict and characterize the folding and functionality of strand swapping in mitoNEET. We demonstrate that a strand unswapped conformation is kinetically accessible and that multiple levels of control are employed to regulate the conformational dynamics of the system. Environmental factors such as temperature can shift route preference toward the unswapped pathway. Additionally we see that a region recently identified as contributing to frustration in folding acts as a regulatory hinge loop that modulates conformational balance. Interestingly, strand unswapping transfers strain specifically to cluster-coordinating residues, opening the cluster-coordinating pocket. Strengthening contacts within the cluster-coordinating pocket opens a new pathway between the swapped and unswapped conformation that utilizes cracking to bypass the unfolded basin. These results suggest that local control within distinct regions affect motions important in regulating mitoNEET's 2Fe-2S clusters.