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Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses

Author

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  • Yuki Toyama

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
    Japan Biological Informatics Consortium (JBiC), Aomi)

  • Hanaho Kano

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo)

  • Yoko Mase

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo)

  • Mariko Yokogawa

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
    Present address: Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo 105-8512, Japan)

  • Masanori Osawa

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
    Present address: Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo 105-8512, Japan)

  • Ichio Shimada

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo)

Abstract

Heterotrimeric guanine-nucleotide-binding proteins (G proteins) serve as molecular switches in signalling pathways, by coupling the activation of cell surface receptors to intracellular responses. Mutations in the G protein α-subunit (Gα) that accelerate guanosine diphosphate (GDP) dissociation cause hyperactivation of the downstream effector proteins, leading to oncogenesis. However, the structural mechanism of the accelerated GDP dissociation has remained unclear. Here, we use magnetic field-dependent nuclear magnetic resonance relaxation analyses to investigate the structural and dynamic properties of GDP bound Gα on a microsecond timescale. We show that Gα rapidly exchanges between a ground-state conformation, which tightly binds to GDP and an excited conformation with reduced GDP affinity. The oncogenic D150N mutation accelerates GDP dissociation by shifting the equilibrium towards the excited conformation.

Suggested Citation

  • Yuki Toyama & Hanaho Kano & Yoko Mase & Mariko Yokogawa & Masanori Osawa & Ichio Shimada, 2017. "Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14523
    DOI: 10.1038/ncomms14523
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    Cited by:

    1. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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