Abstract
G protein-coupled receptors (GPCRs) play critical roles in cellular signal transduction and are important targets for therapeutics. Although these receptors have been intensely studied for quite some time, our understanding about their mechanism of action is still incomplete. GPCR activity has traditionally been viewed within the context of two-state models where the receptor is in equilibrium between a single inactive state and a single active state. This framework is too simple and restrictive to accommodate more recent observations made on these receptors, which instead point to a situation where the receptor can adopt several different active conformational substates with distinct functional effects. Structural and functional evidence for this emerging view is presented in this review. Implications of this emerging view in rationalizing diseased states and in drug discovery are also discussed.
Keywords: Conformational substates, drug action, functional selectivity, receptor activation, receptor pharmacology, membrane protein, signal transduction, two-state model, allosteric effect, ambiguous
Current Medicinal Chemistry
Title: Ensemble of G Protein-Coupled Receptor Active States
Volume: 19 Issue: 8
Author(s): P. S.-H. Park
Affiliation:
Keywords: Conformational substates, drug action, functional selectivity, receptor activation, receptor pharmacology, membrane protein, signal transduction, two-state model, allosteric effect, ambiguous
Abstract: G protein-coupled receptors (GPCRs) play critical roles in cellular signal transduction and are important targets for therapeutics. Although these receptors have been intensely studied for quite some time, our understanding about their mechanism of action is still incomplete. GPCR activity has traditionally been viewed within the context of two-state models where the receptor is in equilibrium between a single inactive state and a single active state. This framework is too simple and restrictive to accommodate more recent observations made on these receptors, which instead point to a situation where the receptor can adopt several different active conformational substates with distinct functional effects. Structural and functional evidence for this emerging view is presented in this review. Implications of this emerging view in rationalizing diseased states and in drug discovery are also discussed.
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Cite this article as:
S.-H. Park P., Ensemble of G Protein-Coupled Receptor Active States, Current Medicinal Chemistry 2012; 19 (8) . https://dx.doi.org/10.2174/092986712799320619
DOI https://dx.doi.org/10.2174/092986712799320619 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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