Calcium channel structure and ligand binding sites. Calcium channel structure and ligand binding sites. (A) Extracellular view of the overall structure of CaVAb (preopen state; PDB ID 4MVQ), a homotetrameric voltage-dependent and calcium-selective channel generated by introducing three negatively charged aspartate residues (side chains in the pore are illustrated) (Tang et al., 2014). The four homologous domains of the α1 subunits of voltage-gated calcium channels likely possess a very similar architecture. Each domain contributes a voltage-sensing domain (VSD) (green, segments S1–S4) and a pore-forming domain, which together form the pore domain (PD) with a central ion conducting pathway for calcium ions (sphere). Each voltage sensor contains four positively charged arginines (side chains illustrated) that sense transmembrane voltage changes. Voltage-sensor movements are transmitted to the PD through a linker (arrow indicates one of them) between helices S4 and S5. (B) Top view of the pore module of CaVAb (pore-forming S5 and S6 helices are shown as cylinders) in the preopen state, with amino acid side chains analogous to those implicated in phenylalkylamine binding (green) and amino acid side chains specific for DHP binding illustrated in blue. The CaVAb structure has been used to illustrate how the analogs of amino acid residues important for drug binding in mammalian channels may form drug binding domains (Catterall and Swanson, 2015).The overlapping binding pocket can explain noncompetitive interactions observed in binding experiments in different tissues (Striessnig et al., 1998). (C) Top view of the CaVAb pore module in the preopen state, with the S5 and S6 segments illustrated as cylinders and amino acid side chains analogous to those implicated in phenylalkylamine binding illustrated in dark green for CaV1.2-specific residues and in light green for CaV-conserved residues. (D) Representation of DHP binding residues as in (C) for phenylalkylamines. Images in (B) to (D) were reproduced from Catterall and Swanson (2015), with permission. Gerald W. Zamponi et al. Pharmacol Rev 2015;67:821-870 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics