Forty years ago, a simple model of allosteric mechanisms (indirect interactions between distinct sites), used initially to explain feedback-inhibited enzymes, was presented by Monod, Wyman, and Changeux. We review the MWC theory and its applications for the understanding of signal transduction in biology, and also identify remaining issues that deserve theoretical and experimental substantiation.

Exactly 50 years ago, biochemists raised the question of the mechanism of the conformational change that mediates “allosteric” interactions between regulatory sites and biologically active sites in regulatory/receptor proteins. Do the different conformations involved already exist spontaneously in the absence of the regulatory ligands (Monod-Wyman-Changeux), such that the complementary protein conformation would be selected to mediate signal transduction, or do particular ligands induce the receptor to adopt the conformation best suited to them (Koshland-Nemethy-Filmer—induced fit)? This is not just a central question for biophysics, it also has enormous importance for drug design. Recent advances in techniques have allowed detailed experimental and theoretical comparisons with the formal models of both scenarios. Also, it has been shown that mutated receptors can adopt constitutively active confirmations in the absence of ligand. There have also been demonstrations that the atomic resolution structures of the same protein are essentially the same whether ligand is bound or not. These and other advances in past decades have produced a situation where the vast majority of the data using different categories of regulatory proteins (including regulatory enzymes, ligand-gated ion channels, G protein-coupled receptors, and nuclear receptors) support the conformational selection scheme of signal transduction.

the presence of several identical subunits assembled Jean-Pierre Changeux* and Stuart J. Edelstein † into a cooperative and symmetrical quaternary struc-Neurobiologie Mole ´culaire ture. Moreover, the conformational transition that such Institut Pasteur protein assemblies undergo was thought to affect pri-75724 Paris Cedex 15 marily the quaternary interactions between subunits, France rather than the tertiary folding within each individual subunit. In other words, the cooperative interactions The concept of allosteric proteins was initially proposed between ligand binding sites would result from the coopto account for paradoxical properties exhibited by cererative transition of the quaternary structure of the moletain bacterial enzymes that catalyze strategic reactions cule. Accordingly, the symmetry properties postulated in biosynthetic pathways. The activity of these enzymes by the model would simply express a characteristic regwas found to be selectively feedback inhibited by the ularity of protein quaternary structure. end product of the pathway, despite its very limited struc-Specifically, the MWC model hypothesizes that: (1) tural resemblance to the substrate (Umbarger, 1956; regulatory proteins in general are oligomers made up of Yates and Pardee, 1956). Subsequently, various in vitro a finite number of identical subunits that occupy equivalent positions and as a consequence possess at least chemical treatments or mutations were found that abolone axis of rotational symmetry (Figure 1A); (2) the alloished the interactions between substrate and regulatory steric oligomers can spontaneously exist in a minimum effector, with little or no loss of activity (Changeux, 1961; of two freely interconvertible and discrete conforma-Gerhart and Pardee, 1962). These observations led to tional states (T R) that differ in the energy of their the proposal that the interactions between both classes intersubunit interactions (quaternary constraint), but of ligand do not result from classical mutual exclusion with conserved molecular symmetry; (3) the affinity and by steric hindrance at a common binding site, but rather activity of the stereospecific sites carried by the oligooccur between topographically and stereochemically mers may differ between the two states, and ligand distinct sites (Changeux, 1961; Monod and Jacob, 1961). binding differentially stabilizes the particular state for The binding of the regulatory ligand to a specific allostewhich it exhibits a higher affinity; and (4) in the absence ric site (Monod and Jacob, 1961), structurally distinct of ligand, the preexisting conformational equilibrium is from the active site, brings about a reversible alteration characterized by an isomerization constant L ϭ (T)/(R), of the conformation of the protein, an allosteric transiand modulation of the conformational equilibrium by tion, that indirectly modifies the properties of the biologiligand binding suffices to generate cooperative ligand cally active site (Monod et al., 1963). This indirect action binding, as well as...

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