期刊
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷 29, 期 7, 页码 965-973出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2011.04.001
关键词
Mitoneet; Autodock; Docking; Fluorescence; Iron-sulfur; Thiazolidinedione
类别
资金
- National Institute Of Diabetes And Digestive And Kidney Diseases [R01DK059766]
Ligands of the thiazolidinedione (TZD) class of compounds, pioglitazone (Actos (TM)) and rosiglitazone (Avandia (TM)) are currently approved for treatment of type 2 diabetes and are known to bind to the PPAR-gamma gamma nuclear receptor subtype. Recent evidence suggesting PPAR-gamma 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 cif 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-gamma 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 angstrom). 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. (C) 2011 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据