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‘7TM Receptor Allostery: Putting Numbers to Shapeshifting Proteins

2009; Elsevier BV; Volume: 30; Issue: 9 Linguagem: Inglês

10.1016/j.tips.2009.06.007

1873-3735

Terry Kenakin,

Protein Structure and Dynamics

Protein allosterism is the change in protein reactivity at one site arising from a molecule binding on the protein at another site. Although allosterism traditionally has been discussed in terms of affinity changes of receptors, the increasing use of functional pharmacological assays makes it mandatory to consider effects on both the affinity and the efficacy. Antagonism of agonist response can occur allosterically by reduction of affinity and/or efficacy but the antagonist will have different properties depending on which of these is primarily affected. This paper discusses the collective behaviors of seven transmembrane (7TM) receptors as allosteric systems that have a modulator (ligand or protein) that interacts and transmits information through a conduit (receptor) to a guest (either other ligand, interacting protein or cytosolic protein). Such receptor allostery can be discussed as vectorial transfers of information from ligand-binding domains ('classical' modulator allosterism) to the cytosol (functional selectivity) and along the plane of the membrane (receptor dimerization).'It is certain that all bodies whatsoever....have perception; for when one body is applied to another…evermore a perception precedeth operation…'Sir Francis Bacon, 1620 Protein allosterism is the change in protein reactivity at one site arising from a molecule binding on the protein at another site. Although allosterism traditionally has been discussed in terms of affinity changes of receptors, the increasing use of functional pharmacological assays makes it mandatory to consider effects on both the affinity and the efficacy. Antagonism of agonist response can occur allosterically by reduction of affinity and/or efficacy but the antagonist will have different properties depending on which of these is primarily affected. This paper discusses the collective behaviors of seven transmembrane (7TM) receptors as allosteric systems that have a modulator (ligand or protein) that interacts and transmits information through a conduit (receptor) to a guest (either other ligand, interacting protein or cytosolic protein). Such receptor allostery can be discussed as vectorial transfers of information from ligand-binding domains ('classical' modulator allosterism) to the cytosol (functional selectivity) and along the plane of the membrane (receptor dimerization).'It is certain that all bodies whatsoever....have perception; for when one body is applied to another…evermore a perception precedeth operation…'Sir Francis Bacon, 1620 refers to the molecule imposing the allosteric change on the receptor. The response can result in a change in receptor behavior from blockade to potentiation of signals. refers to the second molecule binding to the receptor that senses the altered receptor state. It should be noted that allosteric effects are reciprocal and that the guest, in turn, imposes the same thermodynamic effect on the modulator–receptor interaction (from that standpoint, the guest becomes the modulator and the modulator becomes the guest). refers to a guest that can be used to sense the receptor alteration. Traditional probe molecules are agonists or radioligands. Thus, aplaviroc is a modulator imposing its effects, through the CCR5 receptor, on CCL3 (the guest) in blocking CCL3 binding. refers to the equilibrium dissociation constant of the modulator–receptor complex in the absence of guest; that is, the 'bare' affinity of the molecule binding to the receptor protein in the absence of a guest molecule. It should be noted that in intact cellular systems where the guest is a G-protein, it might not be possible to measure this affinity since the guest is an integral part of the system. refers to the observed affinity of the modulator in the presence of the guest where the allosteric effect of the guest is imposed on the receptor. The observed affinity depends upon the concentration of the guest and will be modified by α, the co-operativity constant for differences in affinity between the receptor with the modulator bound and not bound, that is, KA/Kobserved = α. The difference in the probe efficacy in the presence and absence of modulator bound to the receptor. Value of τ for the allosteric agonist producing a direct agonism as a fraction of the τ value of the probe agonist. Index of the effects of an allosteric modulator on responses to an agonist as defined by Ehlert [14]. Specifically it is the ratio of the product of the maximum of the modulated response multiplied by the EC50 of the control curve and the maximum of the control response multiplied by the EC50 of the modulated curve. A plot of Log RA versus Log [modulator] yields an asymptote of Log (αβ) (Box 1). Pairings of receptor in the cell membrane that function as a unit to yield possibly unique signaling and binding properties. Homodimers are pairs of the same receptor type, heterodimers of different receptor types. Each receptor in the dimer is referred to as a protomer.