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Review
. 2012 Mar;165(6):1659-1669.
doi: 10.1111/j.1476-5381.2011.01749.x.

Biased signalling and allosteric machines: new vistas and challenges for drug discovery

Terry P Kenakin  1
Affiliations
Review

Biased signalling and allosteric machines: new vistas and challenges for drug discovery

Terry P Kenakin. Br J Pharmacol. 2012 Mar.

Abstract

Seven transmembrane receptors (7TMRs) are nature's prototype allosteric proteins made to bind molecules at one location to subsequently change their shape to affect the binding of another molecule at another location. This paper attempts to describe the divergent 7TMR behaviours (i.e. third party allostery, receptor oligomerization, biased agonism) observed in pharmacology in terms of a homogeneous group of allosteric behaviours. By considering the bodies involved as a vector defined by a modulator, conduit and guest, these activities can all be described by a simple model of functional allostery made up of the Ehlert allosteric model and the Black/Leff operational model. It will be shown how this model yields parameters that can be used to characterize the activity of any ligand or protein producing effect through allosteric interaction with a 7TMR.

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Figures

Figure 1
Figure 1
Linkage models for receptor function. Receptors are assumed to exist in two states: active (with respect to coupling to G-proteins to induce response denoted [Ra]) and inactive ([Ri]). The ligand A binds to the receptor thereby co-binding with G-proteins. It can be seen that the presence of ligand A on the receptor changes the interaction constants of the receptor by a factor α for the extended ternary complex model and δγ for the cubic ternary complex model. Since α and δγ values can be unique to the ligand A, this allows each ligand to stabilize a unique conformation. The term ‘two state’ thus refers only to the species Ra and Ri and not to the response capability of the system in the presence of agonists.
Figure 2
Figure 2
An allosteric system consisting of a modulator binding to the receptor (conduit) to affect the interaction of a guest with the same receptor. The modulator and guest nomenclature is interchangeable since the energy of interaction through the conduit is equal magnitude and bidirectional. The modulator/guest nomenclature identifies a vector for purposes of identifying specific receptor effects.
Figure 3
Figure 3
Complexation of receptors along the plane of the cell membrane. (A) Receptor functioning as a modulator to affect the interaction of an agonist with another receptor and signalling guest molecules in the cell. (B) Receptor hetero- or homodimer functioning as a new conduit to allow a modulator (agonist) for one receptor to affect a signalling interaction with the other protomer in the dimer.
Figure 4
Figure 4
Allosteric system with the allosteric vector directed towards the cytosol. Modulators (agonists) bind to the conduit to transmit energy to cytosolic signalling proteins as guests. The conformation of the conduit dictates differential interaction with each guest to produce possible bias in activation.
Figure 5
Figure 5
Possible outcomes of effect for allosteric modulators with no direct agonist activity; curves calculated with equation 2 (Em= 100; τ= 3; n = 1.6; KA= 10 µM; KB= 10 nM). Panels from top row–left: (α= 30/β= 5) (α= 1/β= 5) (α= 0.01/β= 5), middle row–left (α= 30/β= 1) (α= 30/β= 1) (middle panel, no curves: (α= 1/β= 1) (α= 0.01/β= 1), bottom row–left (α= 30/β= 0.3) (α= 1/β= 0.3) (α= 0.01/β= 0.3).
Figure 6
Figure 6
Possible outcomes of effect for allosteric modulators with direct agonist activity; curves calculated with equation 2 (Em= 100; τ= 3; n = 1.6; KA= 10 µM; KB= 10 nM; τB= 0.25). Panels from top row–left: (α= 30/β= 5) (α= 1/β= 5) (α= 0.01/β= 5), middle row–left: (α= 30/β= 1) (middle panel; α= 1/β= 1) (α= 0.01/β= 1), bottom row–left (α= 30/β= 0.3) (α= 1/β= 0.3) (α= 0.01/β= 0.3).
Figure 7
Figure 7
Biased agonism in terms of the functional allosteric model. (A) The agonist is a modulator labelled M interacting with a receptor conduit, which also interacts with two guests labelled Gα (for a cAMP response) and β-arrestin for an association with β-arrestin. (B) Upon binding of agonist M, the affinity of the conduit changes in accordance with αG and αB for the particular agonist. The quality of action of the couplers also changes in accordance with βG and βB. (C and D) System parameters: Em= 1; [ϕ]= 0.001 for G-protein/0.002 for β-arrestin; n = 1.6; τ= 1 for G-protein / 0.3 for β-arrestin. Kϕ= 0.03 for both G-protein and β-arrestin. For agonist 1 (modulator M1: KM= 10−6 for unliganded receptor, α= 2000; β= 0.3). For agonist 2 (modulator M2: KM= 10–6 for unliganded receptor, α= 1000; β= 0.6). (E) Bias plot of β-arrestin response (ordinates) as a function of cAMP response (abscissa) for agonists 1 and 2 from panels C and D.
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