Alcohol-binding sites in distinct brain proteins: The quest for atomic level resolution

Rebecca J. Howard, Paul A. Slesinger, Daryl L. Davies, Joydip Das, James R. Trudell, R. Adron Harris

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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.

Original languageEnglish
Pages (from-to)1561-1573
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Issue number9
StatePublished - Sep 2011
Externally publishedYes


  • GIRK
  • Glycine receptor
  • IRK
  • Ligand-gated ion channel
  • Protein binding
  • Protein kinase C
  • Protein structure
  • TRP channel


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