@article {312565,
	title = {Biased Allostery},
	journal = {Biophys J},
	volume = {111},
	number = {5},
	year = {2016},
	month = {Sep 06},
	pages = {902-8},
	abstract = {<p>G-protein-coupled receptors (GPCRs) constitute a large group of integral membrane proteins that transduce extracellular signals from a wide range of agonists into targeted intracellular responses. Although the responses can vary depending on the category of G-proteins activated by a particular receptor, responses were also found to be triggered by interactions of the receptor with β-arrestins. It was subsequently discovered that for the same receptor molecule (e.g., the β-adrenergic receptor), some agonists have a propensity to specifically favor responses by G-proteins, others by β-arrestins, as has now been extensively studied. This feature of the GPCR system is known as biased agonism and is subject to various interpretations, including agonist-induced conformational change versus selective stabilization of preexisting active conformations. Here, we explore a complete allosteric framework for biased agonism based on alternative preexisting conformations that bind more strongly, but nonexclusively, either G-proteins or β-arrestins. The framework incorporates reciprocal effects among all interacting molecules. As a result, G-proteins and β-arrestins are in steric competition for binding to the cytoplasmic surface of either the G-protein-favoring or β-arrestin-favoring GPCR conformation. Moreover, through linkage relations, the strength of the interactions of G-proteins or β-arrestins with the corresponding active conformation potentiates the apparent affinity for the agonist, effectively equating these two proteins to allosteric modulators. The balance between response alternatives can also be influenced by the physiological concentrations of either G-proteins or β-arrestins, as well as by phosphorylation or interactions with positive or negative allosteric modulators. The nature of the interactions in the simulations presented suggests novel experimental tests to distinguish more fully among alternative mechanisms.</p>
},
	isbn = {0006-3495},
	url = {https://www.ncbi.nlm.nih.gov/PubMed/27602718},
	author = {Edelstein, SJ and Changeux, JP}
}
