Retinal Flip in Rhodopsin Activation?

Feng, Jun; Brown, Michael F.; Mertz, Blake

doi:10.1016/j.bpj.2015.04.040

Cited by 14 publications

(16 citation statements)

References 19 publications

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“…The value may be positive or negative, reflecting an influx or efflux that depends on the polymer size (Figure 2 e). Our previous molecular dynamics (MD) simulations [9a] (Figure 2 f) give a physical view of the water influx upon activation, which may occur as early as in the MI state, [26] and is consistent with water release from MII in the back direction [9b] . Movement of transmembrane (TM) helix H6 away from the helical bundle [16a, 17a,b, 27] (Figures 1 a,c) yields a reversible influx of water into the G t binding cleft and solvent channel to the retinal ligand (Figure 2 f).…”

Section: Resultssupporting

confidence: 74%

Activation of the G‐Protein‐Coupled Receptor Rhodopsin by Water

et al. 2020

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Visual rhodopsin is an important archetype for G‐protein‐coupled receptors, which are membrane proteins implicated in cellular signal transduction. Herein, we show experimentally that approximately 80 water molecules flood rhodopsin upon light absorption to form a solvent‐swollen active state. An influx of mobile water is necessary for activating the photoreceptor, and this finding is supported by molecular dynamics (MD) simulations. Combined force‐based measurements involving osmotic and hydrostatic pressure indicate the expansion occurs by changes in cavity volumes, together with greater hydration in the active metarhodopsin‐II state. Moreover, we discovered that binding and release of the C‐terminal helix of transducin is coupled to hydration changes as may occur in visual signal amplification. Hydration–dehydration explains signaling by a dynamic allosteric mechanism, in which the soft membrane matter (lipids and water) has a pivotal role in the catalytic G‐protein cycle.

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Section: Resultssupporting

confidence: 74%

Activation of the G‐Protein‐Coupled Receptor Rhodopsin by Water

et al. 2020

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“…21 Our follow-up study using docking allowed us to overcome the timescale and energy limitations that are common to MD simulations when identifying rare events of interest, in this case the entrance of 11-cis retinal into the opsin channel and release of all-trans retinal from the apoprotein, through the use of a path-and time-independent search algorithm.…”

Section: Discussionmentioning

confidence: 99%

Explaining the mobility of retinal in activated rhodopsin and opsin

Mertz

Feng

Corcoran

et al. 2015

Photochem Photobiol Sci

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Rhodopsin, the mammalian dim light photoreceptor, is the canonical model for G protein-coupled receptors. Activation of rhodopsin occurs when the covalently bound inverse agonist, retinal, absorbs a photon and undergoes an 11-cis to all-trans isomerization. Two critical components of the visual cycle occur with the (1) hydrolytic release of all-trans retinaldehyde and subsequent (2) uptake of 11-cis retinaldehyde to reform the Schiff base linkage in the apoprotein opsin. Two pores on the surface of opsin are connected via the retinal channel, as discovered upon solution of the X-ray crystal structure (Park et al., Nature, 2008), and could serve as potential entryways for uptake and release. Using molecular dynamics simulations, we examined the behavior of rhodopsin in the Meta-II conformation (active) under Meta-I conditions (inactive), and discovered that the retinal binding pocket is flexible enough to allow a 180° rotation along the long axis of the retinal polyene chain. This result reconciles a discrepancy between the known polyene chain orientation from crystallographic and spectroscopic studies and opens the door for further investigation into the intermolecular interactions between the retinal ligand and the apoprotein opsin. Subsequent docking studies of both isomers of retinal into the opsin channel were then conducted to identify the mechanism for uptake and release. Our results suggest that retinal undergoes unidirectional uptake through Pore A and release through Pore B, and that aromatic sidechain interactions play a key role in stabilizing retinal within the opsin channel. These findings are significant in developing our understanding of the retinoid cycle and how ligand-receptor interactions in rhodopsin relate to G protein-coupled receptor activation.

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“…Building on previous work (8), Feng et al (9) have made this problem more tractable through a clever combination of recently published structural data (2), manipulation of the lipid environment, and control of the protonation state of the protein. Beginning from a structure of Meta-II with a flipped, all-trans retinal, the authors selected protonation states and a lipid environment that are expected to back-shift the protein toward the Meta-I conformation.…”

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confidence: 98%

“…The observation that some ligands admit a broader range of protein conformations suggests a possible dynamic mechanism for functional selectivity-activation of one pathway may require a narrower range of conformations, while others respond to a more structurally diverse presentation of the cytoplasmic face. Feng et al (9) provide a template by which a combination of MD and carefully selected experimental information will together connect GPCR dynamics to function.…”

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confidence: 99%

Retinal Flips the Script

Lyman

2015

Biophysical Journal

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Retinal Flip in Rhodopsin Activation?

Cited by 14 publications

References 19 publications

Activation of the G‐Protein‐Coupled Receptor Rhodopsin by Water

Activation of the G‐Protein‐Coupled Receptor Rhodopsin by Water

Explaining the mobility of retinal in activated rhodopsin and opsin

Retinal Flips the Script

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