Structural insights into the N-bundle loop of the CNBD. Left: Ribbon representation of human HCN2 CNBD structure (cAMP-free conformation; (Saponaro et al., 2014). The main structural elements are labeled, including β-roll; the N-terminal helical bundle, which is composed of α-helices E′ and A (αE′ and αA) interconnected by the N-bundle loop (orange), the phosphate-binding cassette (PBC), and α-helix C. Right: Close-up view showing the residues of the N-bundle loop, labeled in orange. The alignment of the N-bundle loop sequences of mammalian HCN and CNG channels (shown here is CNGA1) is reported below. Nonconservative substitutions are highlighted in red.