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Towards a thermodynamic definition of efficacy in partial agonism: The thermodynamics of efficacy and ligand proton transfer in a G protein-coupled receptor of the rhodopsin class

Broadley, Kenneth John, Sykes, Shane C. and Davies, Robin H. 2010. Towards a thermodynamic definition of efficacy in partial agonism: The thermodynamics of efficacy and ligand proton transfer in a G protein-coupled receptor of the rhodopsin class. Biochemical Pharmacology 80 (10) , pp. 1537-1545. 10.1016/j.bcp.2010.07.044

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Abstract

The thermodynamic binding profiles of agonist and antagonist complexes of the 4-hydroxypropanolamine partial agonist, prenalterol, on the chronotropic adrenergic response in guinea-pig right atria were determined over a 15 °C temperature range. The tissue response was compared with data on the ethanolamine agonist, isoprenaline, given by binding studies in a number of rat tissues. Utilising the residue conservatism surrounding the known active conformers bound to either of two aspartate residues (α-helices II, III) in both receptors (β1, β2) and species (guinea-pig, rat and human), no significant deformation in the extended side chain could be found in prenalterol's agonist binding compared to isoprenaline. Antagonist binding gave a highly favourable entropy contribution at 30.0 °C of −4.7 ± 1.2 kcal/mol. The enthalpy change between bound agonist and antagonist complexes, a function of the efficacy alone, was −6.4 ± 1.1 kcal/mol, coincident with the calculated intrinsic preference of a primary/secondary amine–aspartate interaction for a neutral hydrogen-bonded form over its ion pair state, giving values of 6.3–6.6 kcal/mol with calculations of good quality, a figure expected to be close to that shown within a hydrophobic environment. Delivery of a proton to a conserved aspartate anion (α-helix II) becomes the critical determinant for agonist action with resultant proton transfer stabilisation dominating the enthalpy change. A proposed monocation-driven ligand proton pumping mechanism within the ternary complex is consistent with the data, delivery between two acid groups being created by the movement of the cation and the counter-movement of the ligand protonated amine moving from Asp 138 (α-helix III) to Asp 104 (α-helix II).

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Thermodynamics; efficacy; agonist; antagonist binding enthalpies; ligand proton transfer; rhodopsin receptors.
Publisher: Elsevier
ISSN: 0006-2952
Last Modified: 04 Jun 2017 06:28
URI: http://orca.cf.ac.uk/id/eprint/60653

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