Three-dimensional Modelling of the Voltage-gated Sodium Ion Channel from Anopheles gambiae Reveals Spatial Clustering of Evolutionarily Conserved Acidic Residues at the Extracellular Sites

• Published in: Current neuropharmacology 2017-11, Vol.15 (8), p.1062-1072
• Main Authors: Vinekar, Rithvik S, Sowdhamini, Ramanathan
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Animals; Anopheles - chemistry; Binding Sites - physiology; Biological Evolution; Biophysics; Computer Simulation; Humans; Hydrogen-Ion Concentration; Models, Molecular; Phylogeny; Sodium Channels - chemistry; Sodium Channels - physiology
• ISSN: 1570-159X; 1875-6190
• DOI: 10.2174/1567201814666161205131213

Background: The eukaryotic voltage-gated sodium channel(e-Nav) is a large asymmetric transmembrane protein with important functions concerning neurological function. No structure has been resolved at high resolution for this protein. Methods: A homology model of the transmembrane and extracellular regions of an Anopheles gambiae para-like channel with emphasis on the pore entrance has been constructed, based upon the templates provided by a prokaryotic sodium channel and a potassium two-pore channel. The latter provides a template for the extracellular regions, which are located above the entrance to the pore, which is likely to open at a side of a dome formed by these loops. Results: A model created with this arrangement shows a structure similar to low-resolution cryoelectron microscope images of a related structure. The pore entrance also shows favorable electrostatic interface. Conclusion: Residues responsible for the negative charge around the pore have been traced in phylogeny to highlight their importance. This model is intended for the study of pore-blocking toxins.