Cooperativity of Allosteric Receptors

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Abstract

Cooperativity of ligand binding to allosteric receptors can be quantified using the Hill coefficient (nH) to measure the sigmoidal character of the binding curve. However, for measurements of the transition between conformational states, nH 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 nH = 1. Therefore, binding curves with nH > 1 provide a direct measure of cooperativity. For the dependence of the conformational state on ligand concentration, curves with nH>1 are observed, but in virtually all cases, the equivalent allosteric monomer has a value of nH < 1. The ratio of the two nH values defines the effective cooperativity and always corresponds to nH = N (the number of protomers in the oligomer) for concerted transitions as specified by the Monod–Wyman–Changeux model. Dose–response curves for homopentameric α7 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 nH = 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.

Graphical Abstract

Highlights

► The nH values for conformational transitions require a reference state. ► For conformational transitions with nH > 1, for the equivalent monomer: nH < 1. ► The true ratio of oligomer to monomer nH values is equal to the number of monomers. ► Normalization stretches the dose–response curve and increases the value of nH. ► The equivalent monomer concept was first proposed in 1965 by Crick and Wyman.

Abbreviations

GPCR
G-protein-coupled receptor
MWC
Monod–Wyman–Changeux

Keywords

pentameric ligand-gated channels
GPCRs
Hill coefficients
equivalent monomers
allosteric range

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