Allosteric interactions via the orthosteric ligand binding sites in a constitutive G-protein-coupled receptor homodimer. (April 2021)

• Record Type: Journal Article
• Authors: Kukkonen, Jyrki P.
• Is Part Of: Pharmacological research. Volume 166(2021)
• Publication Date: 2021-04
• Subjects: AF-DX 116 N-2-{2-[dipropylaminomethyl]-1-piperidinyl}ethyl)-6-oxo-5H-pyrido2, 3-b(1, 4)benzodiazepine-11-carboxamide (a muscarinic receptor antagonist) -- CHO-K1 Chinese hamster ovary K1 (a cell line) -- GPCR G-protein-coupled receptor -- Nag 26 4'-methoxy-N, N-dimethyl-3'-[N-3-{[2-3-methylbenzamidoethyl]amino}phenyl)sulfamoyl]-(1, 1'-biphenyl)-3-carboxamide (an orexin receptor agonist) -- NAM negative allosteric modulator -- PAM positive allosteric modulator -- TCS 1102 N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-ylsulfanyl]acetyl}-L-prolinamide (an orexin receptor agonist); AF-DX 116 (PubChem CID:107867) -- Human orexin-A (CID:92131430) -- N-methyl scopolamine (PubChem CID:71183) -- Nag 26 (PubChem CID:91810287) -- TCS 1102 (PubChem CID:11960895); G-protein-coupled receptor -- Receptor dimerization -- Receptor theory -- Allosteric modulation -- Mathematical modeling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105116
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: It is known that G-protein-coupled receptors form dimeric or higher order complexes. Co-operative interactions between receptor protomers occur in these complexes. We suggest that the orthosteric binding sites give rise to allosteric behaviour Simulations prove this hypothesis to be reasonable. Novel drugs could enhance or tune down agonist signalling via the orthosteric site. Abstract: I interpret some recent data to indicate that co-operative effects take place between the (identical) orthosteric binding sites in a G-protein-coupled receptor dimer. In the current study, the reasonability of this concept was tested by creating a mathematical model. The model is composed of a symmetrical constitutive receptor dimer in which the protomers are able to affect each other allosterically, and it includes binding, receptor activation and signal amplification steps. The model was utilized for analyses of previous data as well as simulations of predicted behaviour. The model demonstrates the behaviour stated in the hypotheses, i.e. even an apparently neutral receptor ligand can allosterically affect agonist binding or receptor activation by binding to the normal orthosteric ligand binding site. Therewith the speculated allosteric action originating from the orthosteric binding site of the dimeric receptor is a realistic possibility. The results of the simulations and curve fitting constitute a reasonable starting point for further studies, and the model can be utilized to design meaningful experiments to investigate these questions.