Allosteric receptors after 30 years

The history of the allosteric concept is traced from its origins in studies on regulatory enzymes, repressors, membrane proteins, and hemoglobin to its recent applications concerning ionotropic and metabotropic membrane receptors. The principles common to all systems are reviewed, including conformational transitions between symmetric (or pseudo-symmetric) states. Novel features unanticipated by the 1965 Monod-Wyman-Changeux (MWC) model involve (a) ligand binding sites at interfaces between subunits, as found in several classes of allosteric enzymes and pentameric ligand-gated receptors; and (b) effector molecules bound asymmetrically along an axis of symmetry, as in the case of the binding of 2,3-diphosphoglyerate to hemoglobin or the binding of various channel blockers to ionotropic receptors. Special attention is given to the nicotinic receptor, which been extensively characterized with respect to both structure and function. In particular, the roles of natural mutations (congenital myasthenic syndromes and autosomal dominant nocturnal frontal lobe epilepsies) and site-directed mutations in studying the mechanisms of activation and desensitization are reviewed, including the insights derived from constitutively active receptors and gain-of-function mutations. The extents to which these phenomena are consistent with the MWC-type models are considered and compared with «intermediate-state» models. © 2006 Springer.