Recently, we showed that a high resolution structure of the IRK1 cytoplasmic domains contains bound alcohols (which we refer to here as IRK1-MPD)21. The alcohol-binding pocket in the IRK1-MPD complex is formed by hydrophobic amino acid side-chains from three different domains, the N-terminal, the βD-βE ribbon and the βL-βM ribbon (Fig. 1a,b)24. There are seven amino acids that interact with MPD21. Of these, the hydrophobic side-chains of F47, L232, L245 and L330 and Y337 point toward the pocket. In addition to the hydrophobic environment of the pocket, hydrogen bonds may form between one of the hydroxyl groups of MPD and a hydrogen bonding triangle between backbone carbonyl of P244 and OH group of Y242 via a water and between the second hydroxyl group of MPD and the hydroxyl group of Y33721. We compared the high-resolution structure of IRK1 with that of GIRK225 and identified the putative alcohol-binding pocket in GIRK2. The hydrophobic pocket in GIRK2 has significant conservation with amino acids that line the pocket in IRK1 and appears large enough to accommodate MPD similar to IRK1 (Fig. 1c,d).
