Ago-Allosteric Modulation and Other Types of Allostery in Dimeric 7TM Receptors |
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Authors: | Thue W. Schwartz Birgitte Holst |
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Affiliation: | Laboratory for Molecular Pharmacology, Department of Pharmacology, University of Copenhagen and 7TM Pharma A/S, H?rsholm, Denmark |
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Abstract: | Conventionally, an allosteric modulator is neutral in respect of efficacy and binds to a receptor site distant from the orthosteric site of the endogenous agonist. However, recently compounds being ago-allosteric modulators have been described i.e., compounds acting both as agonists on their own and as enhancers for the endogenous agonists in both increasing agonist potency and providing additive efficacy—superagonism. The additive efficacy can also be observed with agonists, which are neutral or even negative modulators of the potency of the endogenous ligand. Based on the prevailing dimeric concept for 7TM receptors, it is proposed that the ago-allosteric modulators bind in the orthosteric binding site, but–importantly–in the “other” or allosteric protomer of the dimer. Hereby, they can act both as additive co-agonists, and through intermolecular cooperative effects between the protomers, they may influence the potency of the endogenous agonist. It is of interest that at least some endogenous agonists can only occupy one protomer of a dimeric 7TM receptor complex at a time and thereby they leave the orthosteric binding site in the allosteric protomer free, potentially for binding of exogenous, allosteric modulators. If the allosteric modulator is an agonist, it is an ago-allosteric modulator; if it is neutral, it is a classical enhancer. Molecular mapping in hetero-dimeric class-C receptors, where the endogenous agonist clearly binds only in one protomer, supports the notion that allosteric modulators can act through binding in the “other” protomer. It is suggested that for the in vivo, clinical setting a positive ago-allosteric modulator should be the preferred agonist drug. |
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Keywords: | GPCR G protein coupled receptor Ghrelin receptor TSH receptor MC1 receptor MC4 receptor Melanocortin receptor GABA receptor Glycoprotein hormone receptor Taste receptor Calcium sensor Cinecalcet Umami receptor Zinc ion Artificial sweetener Cyclamate Thermodynamic receptor model |
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