Abstract
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.
Highlights
Ectonucleotidases modulates the cell surface located nucleotides level by hydrolyzing them to their respective nucleosides
E-NTPDase[1,2,3] and 8 consist of two membrane spanning domains with an active site facing extracellularly that catalyzes the hydrolysis of nucleoside triphosphates to their respective diphosphates which are subsequently hydrolyzed to their respective monophosphates[6,7]
Deletion and mutations in amino sequence of ACR regions result in alterations of hydrolysis activity and substrate specificities[12,13,14,15]
Summary
Rat origin E-NTPDase[1] crystal structure (PDB ID 3ZX3) was found to be the most top ranking template structure which exhibited 74% sequence identity with human origin isozyme. Higher the percentage similarity of template structure with target amino acid sequence lower the Cα RMSD observed values. Stereochemical quality of the constructed homology models in terms of their Phi-Psi (Ramachandran) plots revealed that higher the percentage identity of template structure with target amino acid sequence, higher would be the stereochemical quality of the homology models constructed and it will have lower number of residues with bad geometry (outlier region of Phi-Psi plot). Template structure of rat E-NTPDase[2] had the highest percentage identity of 83% with human isozyme, it exhibited highest stereochemical quality with all residues in favored and allowed region. E-NTPDase[3] was found to fluctuate most amongst the second
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