Theoretical Aspects of GPCR–Ligand Complex Pharmacology

Kenakin, Terrence Peter

doi:10.1021/acs.chemrev.5b00561

Cited by 70 publications

(63 citation statements)

References 110 publications

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“…The timescale difference between theory and experiment is due, in our view, to the fact that we have studied only a confined time interval of the entire GPCR signaling cascade whose individual elements comprise at least (1) ligand binding, (2) conformational change of the receptor (preliminary activation or inactivation), (3) interaction between the ligand-complex receptor and the G-protein (full activation), (4) G-protein conformational changes including GDP release and GTP binding, (5) G protein-effector interaction, (6) change in effector activity, and (7) the resulting ion conductance or second messenger concentration changes. 57 Steps 1-3 are dovetails with the ternary complex model for GPCRs 58,59 and correspond to the Ri  ARi  ARa schemes of the extended or cubic complex models (Ri, initial state unbound receptor; ARi, ligand-complexed receptor in the initial state; ARa, ligand-complexed receptor in the active/inactive state). We may add receptor oligomerization between steps 2 and 3 when applicable.…”

Section: Discussionmentioning

confidence: 99%

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

Herrera-Zúñiga¹,

Moreno-Vargas²,

Ballaud³

et al. 2019

Preprint

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In this work, we study the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic polysaturated ordered lipid. Three systems were prepared: the apo receptor, representing the constitutively active receptor; and two holo-receptors -the receptor coupled to the antagonist/inverse agonist ciproxifan and representing the inactive state of the receptor, and the receptor coupled to the endogenous agonist histamine and representing the active state of the receptor.An extensive analysis of the simulation shows that the three states of H3R present significant structural and dynamical differences, as well as a complex behavior given that the measured properties interact in multiple and inter-dependent ways. In addition, the simulations describe an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.

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Section: Discussionmentioning

confidence: 99%

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

Herrera-Zúñiga¹,

Moreno-Vargas²,

Ballaud³

et al. 2019

Preprint

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“…Fig. 7 shows |V (J)| = 8 so 7 parameters are inherited from the monomer (κe 4 = K A , κe 6 = αK A , κe 8 The concepts and notation introduced here amount to a theoretical framework for allostery in oligomeric receptors composed of any number of identical monomers. For clarity we have used the (perhaps over-simple) ternary complex model dimer and tetramer as running examples, but the approach is completely general.…”

Section: Discussionmentioning

confidence: 99%

“…Equilibrium receptor-occupancy models are used by pharmacologists to quantify changes in ligand affinity and efficacy, and various modes of activation of GPCRs, and to clarify mechanistic hypotheses regarding drug action (3)(4)(5)(6)(7)(8). Pharmaceuticals that allosterically modulate GPCRs are of therapeutic interest due to their potential for greater subtype specificity than orthosteric ligands (9,10).…”

Section: Introductionmentioning

confidence: 99%

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Allostery in oligomeric receptor models

Smith

2018

Preprint

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We show how equilibrium binding curves of receptor heterodimers and homodimers can be expressed as rational polynomial functions of the equilibrium binding curves of the constituent monomers, without approximation and without assuming independence of receptor monomers. Using a distinguished spanning tree construction for reduced graph powers, the method properly accounts for thermodynamic constraints and allosteric coupling between receptor monomers.Guanine nucleotide-binding protein (G protein) coupled receptors (GPCRs) are the largest family of signaling proteins in the mammalian genome and targets for therapeutic drugs (1, 2). When GPCRs are activated by extracellular agonists, they interact with heterotrimeric G proteins to regulate downstream second messenger and protein kinase cascades; notably, cyclic-adenosine monophosphate (cAMP), inositol 1,4,5-triphosphate (IP 3 ), and diacylglycerol (DAG). For example, agonist binding to the β 2 -adrenergic receptor (β 2 AR) stimulates adenylate cyclase (AC) and generates cAMP. Agonist binding to the β 2 AR leads to conformational changes in the 7-transmembrane receptor that destabilize the nucleotidebinding pocket of the G-protein α s -subunit to release GDP, prior to GTP binding and activation of G proteins. G-protein binding to the 7-transmembrane receptor, in turn, changes the affinity of ligand binding (3).Equilibrium receptor-occupancy models are used by pharmacologists to quantify changes in ligand affinity and efficacy, and various modes of activation of GPCRs (4-8). Allosteric modulators of GPCRs are of therapeutic interest due to their potential for greater specificity than agonist and antagonist orthosteric ligands (9). Indeed, allosteric modulators hold promise for treating numerous CNS disorders, including schizophrenia (10, 11).Evidence for clustering of GPCRs has been obtained using various experimental methods, including radioligand binding, coimmunoprecipitation, and fluorescence resonance energy transfer microscopy (FRET) (12-14). Indeed, some GPCRs are obligate dimers (e.g., the GABA B receptor and taste receptors for sweet and umami responses) (15-17). The physical interactions between monomeric units of GPCR oligomers are likely to be important determinants in the mechanism of receptor activation (18)(19)(20). It is widely believed that dimerization and higher-order complexing diversifies GPCR signaling (21-23). Although mathematical analysis has provided specific insights into the complexity of allosteric interactions of receptor oligomers (24, 25), a deeper theoretical understanding of oligomeric signaling could lead to further opportunities for pharmacological intervention. This paper introduces a novel theoretical framework for understanding allostery and thermodynamic constraints in oligomeric receptor models that are composed of any num- ber of identical monomers. The framework allows equilibrium occupancy measures (i.e., binding curves) of receptor homodimers to be expressed in terms of the properties of constituent monomers, without appro...

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“…Here too, lesser suppression of the SWT on the first water rinse by high potency agonists might be due to a fraction of the sweetener remaining bound to the receptor as rinsing continues. Conversely, it is possible the higher potency sweeteners have a higher affinity for the receptor which stabilizes different tertiary receptor conformations and that these conformational differences alter the manner in which the allosteric modulator (lactisole) interacts with the receptor complex, which has been observed for other GPCR systems [39]. …”

Section: Discussionmentioning

confidence: 99%

Differential modulation of the lactisole ‘Sweet Water Taste’ by sweeteners

Alvarado¹,

Nachtigal²,

Slack³

et al. 2017

PLoS ONE

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Pre-exposure to taste stimuli and certain chemicals can cause water to have a taste. Here we studied further the ‘sweet water taste’ (SWT) perceived after exposure to the sweet taste inhibitor lactisole. Experiment 1 investigated an incidental observation that presenting lactisole in mixture with sucrose reduced the intensity of the SWT. The results confirmed this observation and also showed that rinsing with sucrose after lactisole could completely eliminate the SWT. The generalizability of these findings was investigated in experiment 2 by presenting 5 additional sweeteners before, during, or after exposure to lactisole. The results found with sucrose were replicated with fructose and cyclamate, but the 3 other sweeteners were less effective suppressors of the SWT, and the 2 sweeteners having the highest potency initially enhanced it. A third experiment investigated these interactions on the tongue tip and found that the lactisole SWT was perceived only when water was actively flowed across the tongue. The same experiment yielded evidence against the possibility that suppression of the SWT following exposure to sweeteners is an aftereffect of receptor activation while providing additional support for a role of sweetener potency. Collectively these results provide new evidence that complex inhibitory and excitatory interactions occur between lactisole and agonists of the sweet taste receptor TAS1R2-TAS1R3. Receptor mechanisms that may be responsible for these interactions are discussed in the context of the current model of the SWT and the possible contribution of allosteric modulation.

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Theoretical Aspects of GPCR–Ligand Complex Pharmacology

Cited by 70 publications

References 110 publications

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

Allostery in oligomeric receptor models

Differential modulation of the lactisole ‘Sweet Water Taste’ by sweeteners

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