Flapping loops: roles for hinges in a ligand-binding domain of the nicotinic receptor

One of the goals of molecular pharmacology is to understand the machinery that converts information about the presence of a chemical (binding) to a functional consequence. Agonists are drugs that bind to their molecular targets and cause conformational changes underlying activation of the target. Inevitably, therefore, it can be difficult to disentangle the affinity of the agonist for the target from its efficacy in producing the ensuing conformational change. Efficacy depends on two factors: the intrinsic equilibrium between active and inactive states in the absence of agonist, and the energy contributed by the agonist as a result of the relative affinities of agonist for the active and inactive states. These difficulties are particularly frustrating when the goal is to determine the role(s) that particular residues in a target protein have in shaping the overall efficacy of a drug: how is it possible to unambiguously distinguish a role in determining intrinsic efficacy from one in determining relative affinity? This perspective highlights a research article in this issue (p. 351) that demonstrates a quantitative approach to the resolution of this problem in the case of activation of the muscle nicotinic receptor. This elegant (if demanding) approach involves determining, separately, the consequences of specific mutations on gating in the unliganded and liganded states.