Fig. 1. BPV, LCM, and CBZ bind to the same site beneath the intracellular gate (site BIG).
a Distinct densities for the three drugs at site BIG. From left to right, the chemical structures (ball and sticks) and corresponding densities (semi-transparent cloud) are shown for GDN (Nav1.7-apo, PDB code: 7W9K), bupivacaine (BPV, brown), lacosamide (LCM-1, grey), and carbamazepine (CBZ, purple). The densities for the small molecules are presented at similar levels in Chimera, 5 σ for GDN, 4 σ for BPV, 4 σ for LCM-1, and 4.5 σ for CBZ. For visual clarity, only part of the S6I and S6III segments are shown. b The three drugs overlay at Site BIG. A bottom view (left) and a side view (right) of the superimposed pore domain (PD, domain colored) with bound drugs (BPV, LCM, and CBZ) are shown. The same color scheme for the four repeats is applied throughout the manuscript. c Drugs at site BIG directly block the intracellular gate. Shown here is a cross-section view of ligand-bound Nav1.7 PD in an electrostatic surface representation. Two distinct binding poses are observed for LCM (grey spheres), one at site BIG (LCM-1) and the other below the SF (LCM-2). d Further contracted intracellular gate in the presence of the site BIG-binding drugs. Left: Structural comparison of Nav1.7-BPV and Nav1.7-apo (silver). Middle: The pore radii of Nav1.7 bound to different ligands are calculated in HOLE and tabulated. Right: The α→ π transition of S6IV and rearrangement of the gating residues, such as Leu398, Leu964, Ile1457 and Ile1756 (shown as ball and sticks), in the presence of BPV lead to gate contraction. LCM and CBZ-bound structures display nearly identical conformations to that of Nav1.7-BPV.