Extended Data Fig. 8: Met-aromatic interactions occur in voltage-gated HCN1 channels.

a, Local structure of HCN1 + propofol, HCN1 closed (PDB 5U6O), and HCN1 crosslinked (PDB 6UQF) around the Met³⁰⁵-Phe³⁸⁹ interaction. The homologous positions Ile³⁰⁷-Ile³⁹² for the CNGA1 structure (PDB 7LFT) are also shown. Approximate distances between atoms (dashed yellow lines) are labeled between methionine, isoleucine, and the adjacent aromatic rings (purple). Propofol is colored in pink and adjacent protomers are in blue and yellow. b, Multiple sequence alignment between human HCN and CNG isoforms. Residue numbering follows the HCN1 amino acid sequence. The methionine, isoleucine, and aromatic positions labeled in panel a are highlighted in red, orange, and blue. A single aliphatic-aromatic interaction (1-bridge) exists in CNG channels which are ligand gated. In contrast, an interaction between methionine with two aromatic residues (2-bridge) occurs in HCN channels which are voltage gated.