Novel ligands that target the mitochondrial membrane protein mitoNEET.
Novel ligands that target the mitochondrial membrane protein mitoNEET.
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DOI：
10.1016/j.jmgm.2011.04.001
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发表时间：
2011-06
影响因子：
2.9
通讯作者：
Yarmush, Martin L.
中科院分区：
文献类型：
--
作者：
Bieganski, Robert M.;Yarmush, Martin L.
噻唑烷二酮（TZD）类化合物的配体，吡格列酮（Actos™）和罗格列酮（Avandia™）目前被批准用于治疗2型糖尿病，并且已知其与PPAR-γ核受体亚型结合。最近的证据表明TZDs的PPAR-γ独立作用导致了一种新的完整的线粒体外膜蛋白mitoNEET的发现。尽管有几个报告的未结合形式的mitoNEET的X射线晶体结构，mitoNEET配体结合位点（LBS）的位置和性质仍然未知。在本研究中，使用分子盲对接（BD）方法，利用程序AutoDock维纳（v 1.0.2）来发现潜在的mitoNEET LBS和新型配体。使用供试化合物罗格列酮对PPAR-γ受体（PDB ID：1 ZGY）进行BD验证，证明AutoDock维纳测定的罗格列酮结合构象与共结晶配体的结合构象匹配良好（重原子的均方根偏差1.45 μ m）。LBS的位置和一般的配体结合相互作用模型被确定，导致发现新的mitoNEET配体。利用纯化的重组mitoNEET蛋白的体外荧光结合试验用于确定预测的mitoNEET配体的结合亲和力，并且所获得的数据与AutoDock维纳结果良好一致。潜在的mitoNEET配体结合位点和新型配体的发现，为mitoNEET-配体复合物的详细结构研究以及特异性针对mitoNEET的新型配体的合理设计开辟了可能性。
Ligands of the thiazolidinedione (TZD) class of compounds, pioglitazone (Actos™) and rosiglitazone (Avandia™) are currently approved for treatment of type 2 diabetes and are known to bind to the PPAR-γ nuclear receptor subtype. Recent evidence suggesting PPAR-γ independent action of the TZDs led to the discovery of a novel integral outer mitochondrial membrane protein, mitoNEET. In spite of the several reported X-ray crystal structures of the unbound form of mitoNEET, the location and nature of the mitoNEET ligand binding sites (LBS) remain unknown. In this study, a molecular blind docking (BD) method was used to discover potential mitoNEET LBS and novel ligands, utilizing the program AutoDock Vina (v 1.0.2). Validation of BD was performed on the PPAR-γ receptor (PDB ID: 1ZGY) with the test compound rosiglitazone, demonstrating that the binding conformation of rosiglitazone determined by AutoDock Vina matches well with that of the cocrystallized ligand (root mean square deviation of the heavy atoms 1.45 Å). The locations and a general ligand binding interaction model for the LBS were determined, leading to the discovery of novel mitoNEET ligands. An in vitro fluorescence binding assay utilizing purified recombinant mitoNEET protein was used to determine the binding affinity of a predicted mitoNEET ligand, and the data obtained is in good agreement with AutoDock Vina results. The discovery of potential mitoNEET ligand binding sites and novel ligands, opens up the possibility for detailed structural studies of mitoNEET–ligand complexes, as well as rational design of novel ligands specifically targeted for mitoNEET.
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