Cystic fibrosis transmembrane conductance regulator chloride channel blockers: Pharmacological, biophysical and physiological relevance

Figure 4 Importance of the number of fixed positive charges in the pore inner vestibule. The importance of electrostatic interactions with the pore inner vestibule is demonstrated by the finding that the strength of block can be decreased or increased by mutations that decrease or increase, respectively, the number of positively charged amino acid side chains in the pore inner vestibule area shown in Figure 3C. A: Block is relatively weak in when the endogenous positive charge is removed, for example as in the K95Q mutation; B: Block is of similar strength to that observed in wild type cystic fibrosis transmembrane conductance regulator when the positive charge is “transplanted” to other, nearby sites, for example as in the double mutants K95Q/I344K, K95Q/V345K, and K95S/S1141K; C: Block is relatively strong when a second positive charge is introduced, for example as in I344K, V345K and S1141K.