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Structural mechanism of GPCR-arrestin interaction: recent breakthroughs

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Abstract

G protein-coupled receptors (GPCRs) are a major membrane receptor family with important physiological and pathological functions. In the classical signaling pathway, ligand-activated GPCRs couple to G proteins, thereby inducing G protein-dependent signaling pathways and phosphorylation by G protein-coupled receptor kinases (GRKs). This leads to an interaction with arrestins, which results in GPCR desensitization. Recently, non-classical GPCR signaling pathways, mediated by GPCR-bound arrestins, have been identified. Consequently, arrestins play important roles in GPCR signaling not only with respect to desensitization but also in relation to G protein-independent signal transduction. These findings have led to efforts to develop functionally biased (i.e. signal transduction biased) GPCR-targeting drugs. One of these efforts is aimed at understanding the structural mechanism of functionally biased GPCR signaling, which includes understanding the G protein-selectivity or arrestin-selectivity of GPCRs. This goal has not yet been achieved; however, great progress has been made during the last 3 years toward understanding the structural mechanism of GPCR-mediated arrestin activation. This review will discuss the recent breakthroughs in the conformational understanding of GPCR-arrestin interaction.

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Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A1A1A05027473).

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  1. School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440746, Republic of Korea

    Ji Young Park, Su Youn Lee, Hee Ryung Kim & Ka Young Chung

  2. College of Pharmacy & Department of Molecular Science and Technology, Ajou University, Suwon, 443721, Republic of Korea

    Min-Duk Seo

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Correspondence to Ka Young Chung.

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Park, J.Y., Lee, S.Y., Kim, H.R. et al. Structural mechanism of GPCR-arrestin interaction: recent breakthroughs. Arch. Pharm. Res. 39, 293–301 (2016). https://doi.org/10.1007/s12272-016-0712-1

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