Model of drug-nucleotide cooperativity for verapamil-induced activation of Pgp-mediated ATP hydrolysis. The figure shows cartoons of Pgp in the “open”, “closed” and “intermediate” conformations in the A,C,E) absence and B,D,F) presence of ATP, and in the presence of C,D) one and E,F) two verapamil molecules. Verapamil molecules are shown as gray diamonds and N represents ATP. The proposed high and low affinity verapamil binding sites of Pgp are shown as H and L, respectively. The horizontal arrows reflect equilibria between the verapamil-bound conformational states of Pgp. The middle vertical arrows reflect the degree of ATP binding to Pgp, while the arrows at the top of the figure and their size represent the degree of verapamil transport.