Glycine Hinges with Opposing Roles at the Acetylcholine Receptor-Channel Transmitter Binding Site

Abstract

Listen

Translate article

The nicotinic acetylcholine receptor-channel (AChR) is an allosteric protein and an important model for understanding how transmitter molecules activate synaptic receptors. The extent to which agonists activate synaptic receptor-channels depends on the intrinsic tendency of the unliganded receptor to open and the amount of agonist binding energy realized in the channel-opening process. We examined mutations of the nicotinic acetylcholine receptor transmitter binding site (alpha subunit loop B) with regard to both of these parameters. alphaG147 is an ‘activation’ hinge where backbone flexibility maintains high values for intrinsic gating, the equilibrium dissociation constant ratio of the resting conformation for agonists and net ligand binding energy. alphaG153 is a ‘deactivation’ hinge that maintains low values for these parameters. alphaW149 (between these two glycines) mainly serves to provide ligand binding energy for gating. A concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions alphaW149 so that it provides physiologically-optimal binding and gating function at the nerve-muscle synapse.