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WIREs Nanomed Nanobiotechnol
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Structure and function of G protein‐coupled receptor oligomers: implications for drug discovery

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G protein‐coupled receptor (GPCR) oligomers are promising targets for the design of new highly selective therapeutics. GPCRs have historically been attractive drug targets for their role in nearly all cellular processes, and their localization at the cell surface makes them easily accessible to most small molecule therapeutics. However, GPCRs have traditionally been considered a monomeric entity, a notion that greatly oversimplifies their function. As evidence accumulates that GPCRs tune function through oligomer formation and protein–protein interactions, we see a greater demand for structural information about these oligomers to facilitate oligomer‐specific drug design. These efforts are slowed by difficulties inherent to studying membrane proteins, such as low expression yield, in vitro stability and activity. Such obstacles are amplified for the study of specific oligomers, as there are limited tools to directly isolate and characterize these receptor complexes. Thus, there is a need to develop new interdisciplinary approaches, combining biochemical and biophysical techniques, to address these challenges and elucidate structural details about the oligomer and ligand binding interfaces. In this review, we provide an overview of mechanistic models that have been proposed to underlie the function of GPCR oligomers, and perspectives on emerging techniques to characterize GPCR oligomers for structure‐based drug design. WIREs Nanomed Nanobiotechnol 2015, 7:408–427. doi: 10.1002/wnan.1319

This article is categorized under:

  • Therapeutic Approaches and Drug Discovery > Emerging Technologies
  • Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Schematic illustrating nonspecific drug–receptor interactions with hetero‐GPCR oligomers. A therapeutic targets a single receptor (receptor A), but elicits multiple nonspecific responses due to receptor A's propensity to form functionally distinct hetero‐oligomers with receptors B, C, or D in membranes.
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Several modes of GPCR oligomer allostery have been experimentally observed. Novel G‐protein coupling is executed through a D2‐D1 heterodimer (a). A trans‐antagonistic interaction exists between A2a‐D2 heterodimer, in which activation of A2a by CGS21680 agonist inhibits D2 signaling through agonist raclopride (b). Homodimeric function rescues signaling for LHR receptors, where one protomer cannot bind to ligand (hCG) and the other cannot couple to G proteins (c). Finally, heterodimer transactivation occurs via endogenous ligand GABA between GABAB1‐GABAB2 receptors(d). Endogenous ligands for monomeric D1, D2, and A2a receptors in (a) and (b) are dopamine (DA) and adenosine (ADO), respectively.
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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