Ethanol's molecular targets

Abstract

Ethanol produces a wide variety of behavioral and physiological effects in the body, but exactly how it acts to produce these effects is still poorly understood. Although ethanol was long believed to act nonspecifically through the disordering of lipids in cell membranes, proteins are at the core of most current theories of its mechanisms of action. Although ethanol affects various biochemical processes such as neurotransmitter release, enzyme function, and ion channel kinetics, we are only beginning to understand the specific molecular sites to which ethanol molecules bind to produce these myriad effects. For most effects of ethanol characterized thus far, it is unknown whether the protein whose function is being studied actually binds ethanol, or if alcohol is instead binding to another protein that then indirectly affects the functioning of the protein being studied. In this Review, we describe criteria that should be considered when identifying alcohol binding sites and highlight a number of proteins for which there exists considerable molecular-level evidence for distinct ethanol binding sites.

Fig. 1

Preferential stabilization of a substate by ethanol binding. In this illustration, two α helices connected by a short linking loop represent the TM2-TM3 helices found in one subunit of a GABA or Gly receptor. (Left) One substate with a narrow left crossing angle between the helices. (Right) A second vibrational substate with a wider left crossing angle is stabilized by binding a molecule of ethanol in a small cavity created by the intersection of the two helices. If the model in the right panel represents the tertiary structure of the open state of the ion channel in a LGIC, binding of ethanol would favor the transition to the open state.

Fig. 2

Butanol at the interhelical binding site in LUSH. [The PDB file of butanol in the binding site of LUSH (1OOH), complete with 329 water molecules, is from Kruse et al. (48).] A subset of nine water molecules within 10 Å of the oxygen atom of butanol (ButOH) was identified with Insight II (Accelrys, San Diego, California); the subset is highlighted using pink van der Waals surfaces. The five amino acid residues identified in the binding pocket of LUSH by Kruse et al. (48) are rendered with stick surfaces showing carbon, green; oxygen, red; nitrogen, blue; and hydrogen, white.