Cooperativity of Allosteric Receptors

Cooperativity of ligand binding to allosteric receptors can be quantified using the Hill coefficient (n(H)) to measure the sigmoidal character of the binding curve. However, for measurements of the transition between conformational states, n(H) values can be misleading due to ambiguity of the reference state. For cooperative ligand binding, the reference state is a hyperbolic curve for a monomer with a single binding site characterized by n(H) = 1. Therefore, binding curves with n(H)> 1 provide a direct measure of cooperativity. For the dependence of the conformational state on ligand concentration, curves with n(H)>1 are observed, but in virtually all cases, the equivalent allosteric monomer has a value of n(H)<1. The ratio of the two n(H) values defines the effective cooperativity and always corresponds to n(H)= N (the number of protomers in the oligomer) for concerted transitions as specified by the Monod-Wyman-Changeux.nnodel. Dose-response curves for homopentameric alpha 7 nicotinic receptors illustrate this relationship for both wild-type and mutant forms. For functional allosteric monomers such as G-protein-coupled receptors, normalization stretches the dose-response curve along the y-axis, thereby masking the allosteric range and increasing the apparent cooperativity to a limit for monomers of n(H) =1. The concepts of equivalent monomer and allosteric range were originally proposed in 1965 by Crick and Wyman in a manuscript circulated among the proponents of allostery, but only now published for the first time in this special issue. (C) 2013 Elsevier Ltd. All rights reserved.