Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding

Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K chan-nels. Here, we homology-modeled voltage- and Ca2-gated K channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in the inner pore of the channels. Monte Carlo minimization predicted that d-tubocurarine can bind in the open pore of both channels with its long axis parallel to the pore axis. The cationic groups of d-tubocurarine can displace K from the ion dehydration site at the selectivity filter. The pre-dicted binding energy of d-tubocurarine in Kv1.3 is less pref-erable than in BK. To test this prediction, the currents through Kv1.3 and BK channels were measured in the absence and presence of d-tubocurarine. Results show that d-tubocurarin