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Function-related conformational dynamics of G protein–coupled receptors revealed by NMR

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Abstract

G protein–coupled receptors (GPCRs) function as receptors for various neurotransmitters, hormones, cytokines, and metabolites. GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a characteristic level of ability to activate or deactivate its target, which is referred to as its efficacy. The ligand efficacies and biased signaling of GPCRs remarkably affect the therapeutic properties of the ligands. However, these features of GPCRs can only be partially understood from the crystallography data, although numerous GPCR structures have been solved. NMR analyses have revealed that GPCRs have multiple interconverting substates, exchanging on various timescales, and that the exchange rates are related to the ligand efficacies and biased signaling. In addition, NMR analyses of GPCRs in the lipid bilayer environment of rHDLs revealed that the exchange rates are modulated by the lipid bilayer environment, highlighting the importance of the function-related dynamics in the lipid bilayer. In this review, we will describe several solution NMR studies that have clarified the conformational dynamics related to the ligand efficacy and biased signaling of GPCRs.

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Acknowledgments

This work is supported by The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP17H06097, JP18H04540, JP16H01531, JP17H04999, JP16H01353, JP15K18843, JP15J12409, and JP17J1142, and the development of core technologies for innovative drug development based upon IT and the development of innovative drug discovery technologies for middle-sized molecules, from the Japan Agency for Medical Research and Development, AMED (I.S.).

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Takumi Ueda, Yutaka Kofuku, Junya Okude, Shunsuke Imai, Yutaro Shiraishi & Ichio Shimada

  2. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan

    Takumi Ueda

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  1. Takumi Ueda
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Correspondence to Ichio Shimada.

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Takumi Ueda declares that he has no conflict of interest. Yutaka Kofuku declares that he has no conflict of interest. Junya Okude declares that he has no conflict of interest. Shunsuke Imai declares that he has no conflict of interest. Yutaro Shiraishi declares that he has no conflict of interest. Ichio Shimada declares that he has no conflict of interest.

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This article is part of a Special Issue dedicated to the “2018 Joint Conference of the Asian Biophysics Association and Australian Society for Biophysics” edited by Kuniaki Nagayama, Raymond Norton, Kyeong Kyu Kim, Hiroyuki Noji, Till Böcking, and Andrew Battle.

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Ueda, T., Kofuku, Y., Okude, J. et al. Function-related conformational dynamics of G protein–coupled receptors revealed by NMR. Biophys Rev 11, 409–418 (2019). https://doi.org/10.1007/s12551-019-00539-w

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