Modeling the Binding of Tetrodotoxin and Saxitoxin to the Nav1.7 Voltage-Gated Sodium Channel

Authors

Isabella G. Fiore, Nova Southeastern UniversityFollow
Smrithi Mukund, Nova Southeastern UniversityFollow
Laasya Buddharaju, Nova Southeastern UniversityFollow

Files

Submission Date

Fall 2023

Abstract

Approximately 1.5 billion people suffer from chronic pain, with 68 million people suffering in the U.S alone. Chronic pain is defined as pain that persists longer than 12 weeks despite medication or treatment. Within the U.S, about 5.5 million cancer patients experience chronic pain. Around 20% of these cancer pains have neuropathic origins and develop from radiation therapy. Halneuron, a new drug currently in development, seeks to provide pain relief to those suffering from chemotherapy-induced neuropathic pain. This drug includes Tetrodotoxin (TTX), a potent neurotoxin found in most species of pufferfish, as its main active ingredient. Our 3D printed model displays the structural details of Tetrodotoxin (TTX) as a pore blocker within the Nav1.7 channel, providing insight into its use as an analgesic. The model also shows the structural differences between TTX and a similar toxin, saxitoxin (STX), which has a lower binding affinity. A toxin produced by algae, STX is most concentrated in mussels and other shellfish that can induce paralytic shellfish poisoning. Both TTX and STX are Nav1.7 channel pore blockers that inhibit pain. TTX and STX were chosen from the Protein Data Bank and related literature studying pain inhibition. The PDB files 6J8J and 6J8H were used to develop a 3D molecular model showing how both toxins bind to the channel and inhibit action potentials. The files were imported to Jmol, where interactions and amino acids were highlighted to display binding differences. Our model contains key features such as the alpha subunit, backbone, and alpha helices of the Nav1.7 channel. The N and C terminals are intracellular, while voltage sensing domains are extracellular. The helix 4 (S4) of each of the voltage sensing domains have their positively charged lysine or arginine residues highlighted. Amino acids in the Nav1.7 receptor that bind to both STX and TTX are shown: Tyr362, Glu364, Arg922, Glu927, Glu930, Thr1409. Amino acids in the Nav1.7 receptor that bind to TTX, but not STX, are highlighted on the backbone: Gly1407, Gly1699, Phe1405, Ala1698. Amino acids in the Nav1.7 receptor that bind to STX but not TTX are highlighted on the backbone: Trp1700, Asp1744. The DEKA motif (Asp361, Glu930, Lys1406, and Ala1698) is marked on the backbone. Lys 1406 is the critical determinant that specifies the selective permeability of sodium over potassium in these voltage gated channels. The linker in between segments III-IV contains the fast inactivation motif (Ile1472, Phe 1473, Met 1471). There are 4 hydrophobic residues of note on the locus of the S6 of VSD IV: Leu398, Leu964, Ile1453, and Tyr1755. The tyrosine forms a down confirmation allowing sodium ions to be pushed through the channel. Overall, constructing this model allowed us to understand and visualize the binding differences between TTX and STX to the Nav1.7 channel, and simultaneously obtain insight regarding future applications in the treatment of pain disorders.

Recommended Citation

Fiore, Isabella G.; Mukund, Smrithi; and Buddharaju, Laasya, "Modeling the Binding of Tetrodotoxin and Saxitoxin to the Nav1.7 Voltage-Gated Sodium Channel" (2023). Protein Modeling Reports. 13.
https://nsuworks.nova.edu/protein_modeling_reports/13