Though specific alcohol-induced conformational changes in the channel protein remain to be determined, our structural analysis between IRK1-MPD structure and that of chimeric KirBac1.3-GIRK1 structure provides some new clues into channel gating24,39. Two different conformational states of GIRK have been described: a putative open state, due to the open position of the G-loops in the cytoplasmic gate24,39 (GIRK1-open, Fig. 8c) and a putative closed state (GIRK1-closed, Fig. 8c). We aligned the IRK1-MPD structure with these two different Kirbac1.3-GIRK1 structures, and discovered that IRK1-MPD structure aligns better with the GIRK1-open in the hydrophobic alcohol-binding pocket (Fig. 8c, zoom). By contrast, the alignment with GIRK1-closed structure shows striking differences in the hydrophobic alcohol pocket. In particular, the side-chains from F46 in the N-terminal domain, L246 in the βD-βE ribbon and L333 in the βL-βM ribbon fill the hydrophobic pocket of the putative closed state of GIRK1. In the open state, however, structural rearrangements of F46, L246, L333 and F338 occur that enable MPD to now fit in the pocket.
