Definitive proof for alcohol interacting directly with ion channels can be obtained from high resolution atomic structures. To date, only a few high-resolution X-ray crystallographic structures exist of ion channels with alcohol bound (Aryal et al., 2009; Howard et al., 2011a; Sauguet et al., 2013). These structures provide a snapshot of the location of alcohol pockets in the channel. However, more detailed experiments are needed to relate the function of alcohol modulation to the physical structure. Nevertheless, these crystal structures have revealed certain fundamental properties of the alcohol pockets. The alcohol pockets are relatively hydrophobic composed of hydrophobic amino acid side chains (e.g., F, L, I) and amino acids that form hydrogen bonds with the hydroxyl in alcohol. Similar pockets have been also described in non-ion channel alcohol targets, such as Drosophila odorant-binding protein LUSH (Kruse et al., 2003), protein kinase C epsilon (Hodge et al., 1999; Newton and Ron, 2007) and alcohol dehydrogenase (Plapp, 2010), suggesting some features of alcohol pockets may be conserved in different types of proteins.
