Figure 1. Structure of voltage-gated  Ca²⁺ channels. (a) 1 subunits form the pore of all voltage-gated  Ca²⁺ channels. Voltage-gated  Ca²⁺ channels can associate with accessory subunits (2-, , ) that control channel gating and modulation by various second messenger pathways. (b) Classical folding model of  Ca²⁺ channel 1 subunits based on secondary structure predictions. Each homologous repeat (I–IV; helices 1–6) contains a pore motif (indicated in blue) that contributes to the formation of a single ion pore (P). This motif is conserved in other cation channels, including bacterial K⁺-channels (panel e). In  Ca²⁺channels, glutamate residues in the pore loops (S5–S6 linkers, red circles) comprise a  Ca²⁺-binding domain that serves as the selectivity filter. (c) Approximate position of the most important amino acid residues forming the DHP drug-binding domain in repeats III and IV of L-type 1 subunits (black circles). (d) In the folded structure, IIIS5, IIIS6 and IVS6 can form a multisubsite drug-binding domain for DHP binding (triangle), for example. (e) Alternative model of the folding structure of a homologous 1 subunit repeat based on the X-ray structure of a bacterial voltage-gated K⁺-channel. Voltage-dependent gating is proposed to result in movement of the voltage-sensor paddle towards the extracellular membrane surface (Jiang et al., 2003).

Figure 2. Chemical structure of L-type  Ca²⁺ channel blockers. The amino acid sequence of Calciseptine is given in single-letter code. Disulfide bridges are indicated.

Figure 3. Structure of selective non-L-type channel blockers. (a) (+)-ECN is a steroid with some selectivity for T-type  Ca²⁺ channels. Mibefradil also blocks high-voltage-activated  Ca²⁺ channels. (b) The amino acid sequences of peptide toxins are given in single-letter code; O, hydroxyproline; –, gaps for alignment; brackets indicate disulfide bond formation; *, amidated carboxyl terminus. (c) Proposed three-dimensional structures of -conotoxin GVIA and MVIIA based on NMR studies (PDB files 2CCO and 1OMG, respectively). Space-filling structures of the peptides were aligned and colour-coded according to Lew et al. 1997 using Raswin Molecular graphics Ver 2.6. Residues mediating N-type  Ca²⁺ channel affinity are coloured. Mutation of red residues reduces affinity >100-fold. Mutation of orange and yellow residues reduces affinity >10-fold.