Conductance properties of the inwardly rectifying channel, Kir3.2: Molecular and Brownian dynamics study

Using the recently unveiled crystal structure, and molecular and Brownian dynamics simulations, we elucidate several conductance properties of the inwardly rectifying potassium channel, Kir3.2, which is implicated in cardiac and neurological disorders. We show that the pore is closed by a hydrophobic gating mechanism similar to that observed in Kv1.2. Once open, potassium ions move into, but not out of, the cell. The asymmetrical current–voltage relationship arises from the lack of negatively charged residues at the narrow intracellular mouth of the channel. When four phenylalanine residues guarding the intracellular gate are mutated to glutamate residues, the channel no longer shows inward rectification. Inward rectification is restored in the mutant Kir3.2 when it becomes blocked by intracellular Mg2 +. Tertiapin, a polypeptide toxin isolated from the honey bee, is known to block several subtypes of the inwardly rectifying channels with differing affinities. We identify critical residues in the toxin and Kir3.2 for the formation of the stable complex. A lysine residue of tertiapin protrudes into the selectivity filter of Kir3.2, while two other basic residues of the toxin form hydrogen bonds with acidic residues located just outside the channel entrance. The depth of the potential of mean force encountered by tertiapin is − 16.1 kT, thus indicating that the channel will be half-blocked by 0.4 μM of the toxin.

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► Crystal structure is in closed configuration and no conduction is observed.
► Pore is closed by a hydrophobic gating mechanism similar to Kv1.2.
► Open channel conductance compares well to experiment.
► Inward rectification due to no negatively charged residues at intracellular mouth.
► Channel is half blocked by 0.4 μM tertiapin.