Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
Sci Rep. 2018 Feb 7;8(1):2581. doi: 10.1038/s41598-018-20971-4.
Ecto-nucleotidase enzymes catalyze the hydrolysis of extracellular nucleotides to their respective nucleosides. Herein, we place the focus on the elucidation of structural features of the cell surface located ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDase1-3 and 8). The physiological role of these isozymes is crucially important as they control purinergic signaling by modulating the extracellular availability of nucleotides. Since, crystal or NMR structure of the human isozymes are not available - structures have been obtained by homology modeling. Refinement of the homology models with poor stereo-chemical quality is of utmost importance in order to derive reliable structures for subsequent studies. Therefore, the resultant models obtained by homology modelling were refined by running molecular dynamic simulation. Binding mode analysis of standard substrates and of competitive inhibitor was conducted to highlight important regions of the active site involved in hydrolysis of the substrates and possible mechanism of inhibition.
外核苷酸酶酶催化细胞外核苷酸水解为各自的核苷。在此，我们重点阐述位于细胞表面的外核苷三磷酸二磷酸水解酶（E-NTPDase1-3 和 8）的结构特征。这些同工酶的生理作用非常重要，因为它们通过调节核苷酸的细胞外可用性来控制嘌呤能信号转导。由于人同工酶的晶体或 NMR 结构尚不可用 - 因此通过同源建模获得了结构。为了获得后续研究的可靠结构，对具有较差立体化学质量的同源模型进行精修至关重要。因此，通过同源建模获得的模型通过运行分子动力学模拟进行了精修。进行了标准底物和竞争性抑制剂的结合模式分析，以突出参与底物水解的活性位点的重要区域以及可能的抑制机制。
