Solid-state 2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin [Biophysics and Computational Biology]

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Solid-state 2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin [Biophysics and Computational Biology]

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05-17-2011, 08:40 PM

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Solid-state 2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin [Biophysics and Computational Biology]

Solid-state 2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin [Biophysics and Computational Biology]

Struts, A. V., Salgado, G. F. J., Brown, M. F....
Date: 2011-05-17

Rhodopsin is a canonical member of the family of G protein-coupled receptors, which transmit signals across cellular membranes and are linked to many drug interventions in humans. Here we show that solid-state 2H NMR relaxation allows investigation of light-induced changes in local ps–ns time scale motions of retinal bound to rhodopsin. Site-specific 2H labels were introduced into methyl groups of the retinal ligand that are essential to the activation process. We conducted solid-state 2H NMR relaxation (spin-lattice, T1Z, and quadrupolar-order, T1Q) experiments in the dark, Meta I, and Meta II states of the photoreceptor. Surprisingly, we find the retinylidene methyl groups exhibit site-specific differences in dynamics that change upon light excitation—even more striking, the C9-methyl group is a dynamical hotspot that corresponds to a crucial functional hotspot of rhodopsin. Following 11-cis to trans isomerization, the 2H NMR data suggest the ?-ionone ring remains in its hydrophobic binding pocket in all three states of the protein. We propose a multiscale activation mechanism with a complex energy landscape, whereby the photonic energy is directed against the E2 loop by the C13-methyl group, and toward helices H3 and H5 by the C5-methyl of the ?-ionone ring. Changes in retinal structure and dynamics initiate activating fluctuations of transmembrane helices H5 and H6 in the Meta I–Meta II equilibrium of rhodopsin. Our proposals challenge the Standard Model whereby a single light-activated receptor conformation yields the visual response—rather an ensemble of substates is present, due to the entropy gain produced by photolysis of the inhibitory retinal lock. Read More

PNAS:
Number: 20
Volume: 108

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