Fig. 6.

Schematic representation of drug inhibition and drug resistance. In the WT channel, 2 adjacent TM helices form the lipid-facing pocket. The drug binds to the tightly assembled pocket in the closed state, making the channel harder to open. The S31N mutation weakens TM helical packing and thereby disrupts the drug pocket. Consequently, drug affinity is dramatically reduced while channel activity is preserved. The fuzzy lines represent increased conformational heterogeneity caused by weaker helical packing. Channel activation requires His-37 protonation at low pH; thus, destabilization of channel assembly is not sufficient for proton flux.