Schemes and models of hERG channels. (A) Schematic of a single hERG channel subunit with six transmembrane (S1–S6) domains, a pore (P) domain that forms the ion conduction pathway and intracellular N- and C-terminal regions. hERG (and other KCNH channels) have an N-terminal PAS domain and a C-terminal CNBHD. The CNBHD contains an intrinsic ligand motif (orange circle). (B) Cryo-EM structure of a single hERG subunit, showing the site of the intrinsic ligand (orange) in the CNBHD (PDB accession no. 5VA2). (C) Cryo-EM structure of a hERG tetramer, showing intersubunit PAS and CNBHD interactions and showing location of intrinsic ligands (orange; PDB accession no. 5VA2). (D) X-ray crystal structure of PAS-CNBHD of KNCH1 (EAG) channels, showing intrinsic ligand (orange) at the PAS domain-CNBHD interface (PDB accession no. 4LLO). (E) Cryo-EM structure of the hERG CNBHD with the intrinsic ligand (orange; PDB accession no. 5VA2). (F) Structurally guided alignment of part of the CNBHD (β roll 5, α B helix, α C helix and the intrinsic ligand) and distal C-terminal region of KCNH family members hERG, mEAG1, and hELK1 with the CNBD of HCN2 channels. Intrinsic ligand residues are within the red box, as indicated (structural alignment: hERG, PDB accession no. 5VA2; mEAG, PDB accession no. 4LLO; and mHCN2, PDB accession no. 3ETQ; and the hELK sequence is included and primary sequence alignment is structurally guided by zElk, PDB accession no. 3UKN).