AlphaFold predictions for GrTX-SIA binding to human Na V 1.6. (A) Cryo-EM structure of human NaV1.6 (PDB accession no. 8FHD) with proposed docking sites for GrTX-SIA (transparent red) on VSDII and VSDIV. Shown is a view from within the plane of the plasma membrane. The NaVβ1 subunit is shown in green. VSDs of the channel are shown in blue and the remainder in grey. GrTX-SIA binding positions are obtained by superposition of AlphaFold models for GrTX-SIA bound to VSDII and VSDIV individually. (B) Same as in panel A, but shows a top view from the extracellular space facing the plasma membrane. (C) Top AlphaFold model for GrTX-SIA (red) bound to VSDIV (blue). Select residues are labeled. (D) AlphaFold model for GrTX-SIA (red) bound to VSDII (blue). This model corresponds to #6 in the AlphaFold model ranking, but is the highest ranked model whereby GrTX-SIA is bound to the extracellular part of VSDII. Select residues are labeled.