Efficiency of an allosteric protein: Multiple affinity-efficacy correlations link agonist binding to nicotinic receptor activation

Receptors signal by switching between resting and active shapes under the influence of agonists. The maximum response produced by an agonist (‘efficacy’) depends on its relative binding strength (‘affinity’) to active versus resting conformations. Efficiency, the logcorrelation between these two agonist properties, is the fraction of binding energy converted into energy for the receptor’s conformational change. In adult muscle nicotinic receptors, efficiencies estimated from 76 concentration-response curves (23 agonists, 53 mutations) segregate into 5 discrete classes (%): 0.56 (17), 0.51(32), 0.45(13), 0.41(26) and 0.31(12). There is a strong linear correlation between affinity and efficacy within each class, but the multiplicity of classes precludes the appearance of any overall relationship. The efficiency class distribution indicates that there are at least 5 resting versus active binding site structural pairs. We discuss efficiency as a quantitative measure of energy coupling between agonist binding and protein conformational change that is fundamental to receptor operation.