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II the Thermodynamics of Efficacy and Ligand Proton Transfer Towards a Thermodynamic Definition of Efficacy in Partial Agonism: II The Thermodynamics of Efficacy and Ligand Proton Transfer in a G Protein-coupled Receptor of the Rhodopsin Class Kenneth J. Broadley, Shane C. Sykes, Robin H. Davies To cite this version: Kenneth J. Broadley, Shane C. Sykes, Robin H. Davies. Towards a Thermodynamic Definition of Efficacy in Partial Agonism: II The Thermodynamics of Efficacy and Ligand Proton Transferina G Protein-coupled Receptor of the Rhodopsin Class. Biochemical Pharmacology, Elsevier, 2010, 80 (10), pp.1537. 10.1016/j.bcp.2010.07.044. hal-00626230 HAL Id: hal-00626230 https://hal.archives-ouvertes.fr/hal-00626230 Submitted on 24 Sep 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: Towards a Thermodynamic Definition of Efficacy in Partial Agonism: II The Thermodynamics of Efficacy and Ligand Proton Transfer in a G Protein-coupled Receptor of the Rhodopsin Class Authors: Kenneth J. Broadley, Shane C. Sykes, Robin H. Davies PII: S0006-2952(10)00583-6 DOI: doi:10.1016/j.bcp.2010.07.044 Reference: BCP 10678 To appear in: BCP Received date: 28-6-2010 Accepted date: 21-7-2010 Please cite this article as: Broadley KJ, Sykes SC, Davies RH, Towards a Thermodynamic Definition of Efficacy in Partial Agonism: II The Thermodynamics of Efficacy and Ligand Proton Transfer in a G Protein-coupled Receptor of the Rhodopsin Class, Biochemical Pharmacology (2010), doi:10.1016/j.bcp.2010.07.044 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Manuscript Efficacy/Proton transfer_II 1 Submission Category (2) Cardiovascular Pharmacology 2 3 4 5 6 7 8 9 10 11 Towards a Thermodynamic Definition of Efficacy in Partial Agonism: II 12 13 14 The Thermodynamics of Efficacy and Ligand Proton Transfer in a G 15 16 Protein-coupled Receptor of the Rhodopsin Class 17 18 19 20 a a a,b 21 Kenneth J. Broadley , Shane C Sykes and Robin H. Davies 22 23 24 25 a) The Welsh School of Pharmacy, The University of Cardiff, P.O.Box 13, 26 Cardiff CF10 3XF, Wales, U.K. 27 28 b) Muscagen Limited, 10 North Road, Cardiff CF10 3DY, Wales, U.K. 29 30 31 32 Acknowledgements 33 34 The authors would like thank Dr J. D. Fitzgerald for his support and scientific 35 36 encouragement and acknowledge the support given to the work by ICI under the 37 38 39 SERC CASE award No. BC/117 (1985). 40 41 42 43 Corresponding Author Dr R.H.Davies Tel 44-(0)2920-875830 44 45 c/o The Welsh School of Pharmacy Mob 44-(0)7961-874149 46 University of Cardiff Fax 44-(0)2920-874149 47 Redwood Building 48 Accepted King Edward VII Avenue Manuscript 49 50 Cathays Park 51 Cardiff CF10 3DY 52 United Kingdom 53 54 55 56 Keywords: Thermodynamics, efficacy; agonist, antagonist binding enthalpies; ligand 57 58 proton transfer; rhodopsin receptors 59 60 61 62 63 1 64 Page 1 of 36 65 1 2 3 4 5 6 Efficacy/Proton transfer_II 7 8 9 10 11 12 A B S T R A C T 13 14 _____________________________________________________________________ 15 16 17 The thermodynamic binding profiles of agonist and antagonist complexes of the 4- 18 19 hydroxypropanolamine partial agonist, prenalterol, on the chronotropic adrenergic response in guinea - 20 21 pig right atria were determined over a 15 temperature range. The tissue response was compared with 22 23 data on the ethanolamine agonist, isoprenaline, given by binding studies in a number of rat tissues. 24 25 Utilising the residue conservatism surrounding the known active conformers bound to either of 26 27 two aspartate residues ( -helices II,III) in both receptors ( 1, 2) and species (guinea-pig, rat and 28 29 human), no significant deformation in the extended sidechain could be found in prenalterol’s agonist 30 31 binding compared to isoprenaline. Antagonist binding gave a highly favourable entropy contribution at 32 33 30.0 C of -4.7 1.2 kcal/mol. 34 35 The enthalpy change between bound agonist and antagonist complexes, a function of the efficacy alone, 36 37 was - 6.4 ± 1.1 kcal/mol, coincident with the calculated intrinsic preference of a primary/secondary 38 39 amine-aspartate interaction for a neutral hydrogen-bonded form over its ion pair state, giving values of 40 41 6.3 - 6.6 kcal/mol with calculations of good quality, a figure expected to be close to that shown within a 42 43 44 hydrophobic environment. Delivery of a proton to a conserved aspartate anion ( -helix II) becomes the 45 46 critical determinant for agonist action with resultant proton transfer stabilisation dominating the 47 48 enthalpy change.Accepted Manuscript 49 50 A proposed monocation-driven ligand proton pumping mechanism within the ternary complex is 51 52 consistent with the data, delivery between two acid groups being created by the movement of the cation 53 54 and the counter-movement of the ligand protonated amine moving from Asp 138 ( -helix III) to Asp 55 56 104 ( -helix II). 57 58 59 60 61 62 63 2 64 Page 2 of 36 65 1 2 3 4 Efficacy/Proton transfer_II 5 6 7 8 1. Introduction 9 10 11 12 13 An interpretation of partial agonism as the result of two bound complexes related to agonist and 14 15 antagonist action existing within a G protein-receptor ternary complex was considered in paper I [1] 16 17 and the requisite concentration-response theory for a compound obeying a hyperbolic relation derived 18 19 using a simple adaptation of the Black and Leff operational model of agonism [2]. A tissue response, 20 21 (the chronotropic in the guinea-pig right atrium) was selected based on data indicating its dominant 22 23 control by the 1-adrenergic receptor under normal conditions of signal amplification (refer also, paper 24 25 I[1]). The advantage of such a description, transposing the observed parameters of binding and efficacy 26 27 into two binding constants related to agonist and antagonist action, lies in temperature variation and the 28 29 determination of the thermodynamic profiles of the respective agonist and antagonist complexes. 30 31 Temperature studies [3-6] using isolated membranes for the binding of ligands to G protein-coupled 32 33 34 receptors complexes utilising -adrenergic receptor sub-types showed linear plots of unit slope over a 25 35 36 C range of temperature offering the prospect of accurate enthalpic changes if sufficient precision were 37 38 attained with a given receptor. While such data contain binding studies on more than one receptor sub- 39 40 type, it was considered here, more illuminating to select a non-specific partial agonist structurally 41 42 related to the natural hormone but to choose the tissue response dominated by a single receptor sub-type. 43 44 Under normal signalling conditions, the chronotropic response in guinea-pig right atria was shown to be 45 46 dominated by the 1-adrenergic receptor with a less than 5% contribution from the 2-receptor. Data 47 48 ‘in vitro’ at 30.0Accepted C on the binding and efficacy ofManuscript the phenoxypropanolamine partial agonist, 49 50 prenalterol to this cardiac -adrenergic receptor were given in the first paper [1]. The precision was 51 1 52 shown to be sufficient for evaluation of the thermodynamics of the respective complexes over a 15 C 53 54 55 range of temperature [1]. 56 57 58 59 60 61 62 63 3 64 Page 3 of 36 65 Efficacy/Proton transfer_II 1 2 3 4 In this second paper, the binding and efficacy of prenalterol, are extended to 25.0 and 40.0 C and the 5 6 thermodynamic profiles of the agonist and antagonist complexes determined. The enthalpic difference 7 8 between the agonist and antagonist complexes which is a function only of the efficacy, will be shown to 9 10 have a simple physical interpretation consistent with a basic criterion for agonist action discussed below. 11 12 13 14 Considerable insight into structural features of ligands using close extra-thermodynamic comparison can 15 16 be obtained by transforming data to a pure hydrocarbon phase reference using appropriate partitioning 17 18 methods which can provide additional insight into the polar and distortional changes observable on 19 20 receptor binding [7]. Using this reference, the thermodynamic profile of the agonist binding of 21 22 prenalterol will be compared with published data for the non-specific 3,4 di-hydroxyphenethanolamine 23 24 agonist, isoprenaline, determined from -adrenergic receptors in a number of rat tissues. The 1-receptor 25 26 residues in guinea-pig, rat and human which surround the known bound ethanolamine conformer within 27 28 4.5 Å of its expected ‘upper’ (Asp138; -helix III) and ‘lower’ (Asp 104; -helix II) positions within 29 30 31 the receptor are all conserved.
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