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Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation

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Abstract

X-ray and magnetic resonance approaches, though central to studies of G protein–coupled receptor (GPCR)-mediated signaling, cannot address GPCR protein dynamics or plasticity. Here we show that solid-state 2H NMR relaxation elucidates picosecond-to-nanosecond–timescale motions of the retinal ligand that influence larger-scale functional dynamics of rhodopsin in membranes. We propose a multiscale activation mechanism whereby retinal initiates collective helix fluctuations in the meta I–meta II equilibrium on the microsecond-to-millisecond timescale.

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Figure 1: Site-specific 2H NMR relaxation illuminates functional dynamics of retinylidene methyl groups within binding pocket of rhodopsin.
Figure 2: Solid-state 2H NMR captures site-specific changes in retinal mobility during light activation of rhodopsin.
Figure 3: 2H NMR relaxation of retinal sheds new light on activation mechanism of rhodopsin.

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Acknowledgements

We thank T.A. Cross, K.P. Hofmann, M. Hong, W.L. Hubbell, L.E. Kay, S.O. Smith and R.W. Pastor for discussions. Retinal was provided by K. Tanaka, S. Krane and K. Nakanishi (Columbia University). Financial support from the US National Institutes of Health (EY012049 and EY018891) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Chemistry, University of Arizona, Tucson, Arizona, USA

    Andrey V Struts & Michael F Brown

  2. Department of Physics, St. Petersburg State University, St. Petersburg, Russia

    Andrey V Struts

  3. Département de Chimie, École Normale Supérieure, Paris, France

    Gilmar F J Salgado

  4. Torrey Pines Institute for Molecular Studies, Fort Pierce, Florida, USA

    Karina Martínez-Mayorga

  5. Department of Physics, University of Arizona, Tucson, Arizona, USA

    Michael F Brown

Authors
  1. Andrey V Struts
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  2. Gilmar F J Salgado
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  3. Karina Martínez-Mayorga
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  4. Michael F Brown
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Contributions

A.V.S. and M.F.B. designed the research. A.V.S. and G.F.J.S. performed the experiments. A.V.S., G.F.J.S., and K.M.-M. analyzed the data. A.V.S. and M.F.B. wrote the paper.

Corresponding author

Correspondence to Michael F Brown.

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The authors declare no competing financial interests.

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Struts, A., Salgado, G., Martínez-Mayorga, K. et al. Retinal dynamics underlie its switch from inverse agonist to agonist during rhodopsin activation. Nat Struct Mol Biol 18, 392–394 (2011). https://doi.org/10.1038/nsmb.1982

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  • DOI: https://doi.org/10.1038/nsmb.1982

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