Identification of the Molecular Site of Ivabradine Binding to HCN4 Channels
Figure 1
Homology models of the hHCN4 channel.
A: Homology models of the TM1/S5-P-TM2/S6 regions of the hHCN4 channel in the closed (left) and open form (right), respectively. Only two of the four subunits are shown for clarity. Residues lining the internal cavity are shown in stick mode and labeled. M508 is also indicated even if it does not point towards the cavity. B: sequence alignment of the TM1/S5-P-TM2/S6 regions of hHCN4 with the corresponding regions of mHCN1, mHCN2, Streptomyces lividans KcsA, and the mammalian K+ channel Kv1.2. The secondary structure elements, as defined in the crystal structure of KcsA, are indicated. P is pore, SF is selectivity filter. Residues of HCN channels identical and similar to those of KcsA and/or Kv1.2 are highlighted by green and yellow boxes, respectively. Residues that face the internal cavity of the hHCN4 channel in the open and closed forms and residues relevant to mHCN2 block by cilobradine [24] and to mHCN1/mHCN2 block by ZD7288 [2],[24],[25] are indicated in red bold font.