Purohit_2011_Mol.Pharmacol_79_351

The extent to which agonists activate synaptic receptor-channels depends on both 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. alphaGly147 is an "activation" hinge where backbone flexibility maintains high values for intrinsic gating, the affinity of the resting conformation for agonists and net ligand binding energy. alphaGly153 is a "deactivation" hinge that maintains low values for these parameters. alphaTrp149 (between these two glycines) serves mainly to provide ligand binding energy for gating. We propose that a concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions alphaTrp149 so that it provides physiologically optimal binding and gating function at the nerve-muscle synapse.