Allosteric Receptors after 30 Years

Abstract

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...

An Extracellular Protein Microdomain Controls Up-regulation of Neuronal Nicotinic Acetylcholine Receptors by Nicotine

“…and ␤4 Subunits-cDNAs encoding the ␤2 and the ␤4 rat subunits were excised as a NotI/XhoI fragment from the clones kindly supplied by J. Boulter and introduced into the pMT 3 vector for expression (26). Synthetic genes coding for the extracellular domain (ECD) of ␤2 and ␤4 were constructed by PCR amplification (pwo-polymerase, Roche Applied Science) using 60-mer oligonucleotides with an overlap of 20 base pairs, containing the minimum set of mutations allowing adequately distributed common restriction sites.…”

“…tinic acetylcholine receptors (nAChRs), 1 a class of pentameric allosteric ligand-gated ion channels engaged in cholinergic nicotinic transmission in the brain (3,4).…”

Comparison of Taurine- and Glycine-induced Conformational Changes in the M2-M3 Domain of the Glycine Receptor

“…In such a mechanism, higher efficacy would be manifested by an increased ability to stabilize the open state. Because extended MWC models can explain many characteristics of LGIC behavior (34), this model is the favored hypothesis for the present study.…”

Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor

“…The glycine receptor (GlyR) is a member of the nicotinic-like LGIC superfamily that includes the nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT 3 R), and ␥-aminobutyric acid (GABA A R) receptors (1,2). Each of these receptors are pentameric complexes arranged around a central ion conducting pore.…”

“…The extracellular domain contains the ligand binding site, which is spatially separate from the M2 domain that lines the ion channel pore of these receptors (3,4). While there is an accumulated body of data on the structures involved in ligand binding (2) and the ion channel pore (2-4), relatively little is known about the structures that may link these two spatially separate domains to effect receptor activation.…”