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

Area of Science:

• Neuropharmacology
• Structural Biology
• Molecular Pharmacology

Background:

• Understanding ethanol's molecular targets in the brain is crucial for its pharmacology.
• Alcohols like ethanol have low potency, interacting transiently and with low affinity, making them difficult to study with traditional methods.
• Atomic-level understanding of alcohol action is hindered by low-affinity interactions.

Purpose of the Study:

• To define the sites and mechanisms of ethanol action on key brain proteins.
• To review recent progress in understanding alcohol-protein interactions.
• To explore common themes in alcohol binding across diverse protein classes.

Main Methods:

• X-ray crystallography
• Structural modeling
• Site-directed mutagenesis

Main Results:

• Identified specific binding sites and mechanisms for ethanol on various brain proteins, including ion channels and protein kinase C epsilon.
• Observed common interaction themes: hydrogen bonding by the hydroxyl group and van der Waals interactions by methylene groups of ethanol.
• Proposed that ethanol binding acts as a 'molecular lubricant,' facilitating low-energy state transitions in proteins.

Conclusions:

• Discrete alcohol-binding sites and interaction regions exist on protein targets.
• Ethanol's molecular pharmacology can be elucidated through integrated structural and mutagenesis approaches.
• The 'molecular lubricant' model provides a framework for understanding ethanol's effects on protein function.