G protein coupled receptors as allosteric proteins and the role of allosteric modulators

GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
Journal of Receptor and Signal Transduction Research (Impact Factor: 2.28). 10/2010; 30(5):313-21. DOI: 10.3109/10799893.2010.503964
Source: PubMed


Seven transmembrane receptors (7TMRs) are proteins that convey signals through changes in conformation. These conformations are stabilized by external molecules (i.e. agonists, antagonists, modulators) and act upon other bodies (termed 'guests') which can be other molecules in the extracellular space, or proteins along the plane of the membrane (receptor oligomerization) or signaling proteins in the cytosol (i.e. G protein, β-arrestin). These elements comprise allosteric systems and a great deal of 7TMR pharmacology can be considered in terms of allosteric behavior. Allosteric ligands acting on 7TMRs possess four unique behaviors that can be valuable therapeutically; (1) the ability to alter the interaction of very large proteins, (2) probe dependence, (3) saturable effect, and (4) induction of separate changes in affinity and efficacy of other ligands. Two of these behaviors (namely probe dependence for CCR5-based HIV-1 entry inhibitors and functional selectivity for biased agonism) will be highlighted with examples.

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    • "Monod (1979) defined allostery as 'the second secret of life' since allostery could be considered important second only to the genetic code (Fenton, 2008), and as mentioned above and discussed in previous papers, the basic phenomenon mediating RRI is allosterism (see Agnati et al., 2005b, 2010a; Kenakin et al., 2010). Allostery, or a 'different shape', according to the classical view, involves coupling of conformational changes between two widely separated binding sites in a protein; hence, allostery allows an extraordinary functional plasticity to proteins, resulting as a crucial mechanism for living cells. "
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    • "One mechanism suggested to account for both termination of signaling and receptor desensitization is receptor phosphorylation and binding of arrestin to the cytosolic parts of the agonist-occupied receptor [5], [6]. According to this model, binding of arrestin causes occlusion of the heterotrimeric G-protein [7], [8], [9], [10]. "
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