Structural changes to Na+/K+-ATPase affecting cardiac glycoside resistance

Abstract

Cardiac glycosides are steroidal toxins comprising the cardenolides and bufadienolides that bind to the sodium-potassium pump (Na+/K+-ATPase) to inhibit ion transport and signaling. Most animals are susceptible to them, but several mutations have been associated with resistance in various species, allowing for the animals to feed on cardiac glycoside-producing plants and animals, and even sequester the toxins for their own protection. Molecular docking studies have been conducted to determine the structural basis for resistance to ouabain, a cardenolide. However, comparable studies have not been conducted with other cardiac glycosides, and subsequent new developments in the availability of high-quality crystal structures have warranted another molecular docking study along similar parameters. Using AutoDock Vina to dock the cardenolide ouabain and the bufadienolide bufalin to Na+/K+-ATPase, I corroborated the previous evidence finding an important role for an asparagine to tyrosine substitution at position 122 in the first extracellular loop of Na+/K+-ATPase, and found seven other single-amino-acid substitutions that may confer cardiac glycoside resistance in a similar matter. However, I also found only weak correlations between results for the different cardiac glycosides and receptors, suggesting the limitations of molecular docking in making inferences about this protein-ligand interaction.