Figure 1

The strategy for reorienting the wild-type BmKTX binding interface to create two de novo peptides, BmKTX-19 and BmKTX-196, with potential new binding interfaces.

A, Toxin evolution-guided drug design strategy and structural features of both peptide blockers and K⁺ channels. B, Sequence alignment of two designed and two known peptide blockers. Widely distributed basic residues are shaded in light blue and characteristically distributed acidic residues are colored pink. C, Known binding interfaces of two potent Kv1.3 peptide inhibitors ADWX-1 (PDB code: 2K4U)⁴² and BmKTX (PDB code: 1BKT)⁴³ and designed binding interfaces of two de novo BmKTX-19 and BmKTX-196 peptides. The basic residues around the peptide binding interfaces and acidic residues in the peptide non-binding interface were labeled. For the reorientation of the BmKTX binding interface by toxin evolution-guided drug design strategy, three key residues, Lys6, Asp19 and Asp33, in wild-type BmKTX and their corresponding residues in the designed BmKTX-19 and BmKTX-196 peptides were focused and framed.