Two different types of alcohol-bound protein structures have been solved previously, the enzymatic/catalytic alcohol dehydrogenase (ADH) and a non-catalytic Drosophila odorant-binding protein, LUSH. In ADH, primary alcohol is coordinated with Zn2+ in a hydrophobic pocket, where it catalyzes the oxidation of alcohol to aldehyde34,35. Mutagenesis studies in the pocket indicated the bulkiness of side-chains in the hydrophobic pocket determines alcohol specificity36. The high-resolution structure of LUSH in complex with small alcohols showed that in addition to hydrophobic interactions, a network of hydrogen bonds help stabilize alcohol in the LUSH alcohol-binding pocket22,37. The hydrophobic pocket in IRK1-MPD has many of the same features of these alcohol-binding pockets. First, hydrophobic amino acids form the pocket and interact intimately with hydrocarbons of the alcohol (Fig. 1b). In GIRK2, mutations of L257 to bulkier amino acids significantly reduced or eliminated alcohol-mediated activation. This finding is consistent with the role of hydrophobic side-chains in determining the size of the alcohol-binding pocket. Second, the IRK1-MPD structure indicates that hydrogen-bonds form between MPD and the backbone carbonyl of P244, Y242 via a water and a hydroxyl of
