The concept of allosteric interaction (1) which was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes contrasts with the classical mechanism of competitive, steric, interaction between ligands for a common site. Accordingly allosteric interactions are indirect interactions that take place between topographically distinct sites and are mediated by a discrete & reversible conformational change of the protein.
The concept was soon extended to membrane receptors for neurotransmitters (2) which behave as «molecular switches» mediating the signal tranduction process at the synapse, which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel (3). Furthermore, pharmacological effectors, referred to as allosteric modulators, such as Ca++ ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel on the nAChR (4). The recent X-ray structures, at atomic resolution, of the resting & active conformations of prokaryotic and eukaryotic homologs of the nAChR, in combination with atomistic molecular dynamics simulations (5) reveal a stepwise quaternary transitions in the transduction process with tertiary changes which modify the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The model emerging from these studies has lead to the conception and development of new pharmacological agents. For example, looking for chemical therapies against Autism, a strategy was elaborated on the basis of brain genes expression data, using the concept of coherent-gene groups controlled by transcription factors (TFs), which resulted in the design of allosteric modulators targeted toward specific TFs expressed at critical steps of brain development (6).
1. Changeux JP (1961) The feedback control mechanisms of biosynthetic L- threonine deaminase by L-isoleucine. Cold Spring Harb Symp Quant Biol 26:313–318 ; Gerhart JC, Pardee AB (1962] The enzymology of control by feedback inhibition. J Biol Chem 237:891–896
2. Changeux (1964) PhD Thesis ; (1965) [On the allosteric properties of biosynthesized l-threonine deaminase. VI. General discussion]. Bull Soc Chim Biol (Paris) 47:281-300.
3. Taly A, Corringer PJ, Guedin D, Lestage P, Changeux JP. (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system Nat Rev Drug Discov. 8:733-50.
4. Corringer, P.J., Poitevin, F., Prevost, M.S., Sauguet, L., Delarue, M., Changeux, J.P.(2012) Structure and pharmacology of pentameric receptor-channels: from bacteria to brain. Structure 20, 941–956
5. Changeux JP (2014) Protein dynamics and the allosteric transitions of pentameric receptor channels. Biophys Rev. 6:311-321 ; Cecchini M, Changeux JP (2014) The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. Neuropharmacology Dec 18. pii: S0028-3908(14)00450-X. doi: 10.1016/j.neuropharm.2014.12.006
6. Tsigelny IF, Kouznetsova VL, Baitaluk M, Changeux JP.(2013) A hierarchical coherent-gene-group model for brain development. Genes Brain Behav. 12:147-65.