Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 35, Issue 9, Pages 1561-1573Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1530-0277.2011.01502.x
Keywords
Protein Binding; Protein Structure; Glycine Receptor; TRP Channel; Protein Kinase C; GIRK; IRK; Ligand-Gated Ion Channel
Categories
Funding
- NIH/NIAAA [F31 AA017042, R21 AA016140-02, R01 AA013890, R01 AA013922, T32 AA007471, R01 AA06399, R01 AA013378, R01 AA018734]
- NIH [R01 GM056653, P41 RR01081]
- University of Southern California School of Pharmacy
Ask authors/readers for more resources
Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmitter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a molecular lubricant for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available