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• W4225376293 abstract "G protein-coupled receptors (GPCRs) are responsible for the transduction of signals across lipid membranes and are the largest family of targets (~35%) for currently approved drugs. They exist as dynamic conformational ensembles with multiple inactive and active conformational substates described by an energy landscape model. Consequently, understanding the modulation of conformational dynamics of GPCRs by soft matter such as membrane lipids and cellular water in the receptor's environment is critical to understanding GPCR efficacy and selectivity. Here we show how membrane lipids and cellular water play crucial roles in shaping the energy landscape of GPCR activation, thus acting as allosteric modulators. We investigated ways in which the receptor hydration level and lipid bilayer composition influence the metarhodopsin equilibrium of the archetypical GPCR rhodopsin in native and POPC recombinant membranes after light activation. Using different polyethylene glycol (PEG) solutions, the osmotic pressure on rhodopsin was varied, while shifting of the metarhodopsin equilibrium was probed using UV-Visible spectroscopy. Our results show a flood of ~80-100 water molecules into the rhodopsin interior during photoactivation, forming a solvent-swollen Meta-II active state. Dehydrating conditions favor Meta-I through the efflux of water from the protein interior yet simultaneously increase bilayer thickness, which should favor Meta-II. Because the osmotic effect on the protein is more significant than the effect of the lipid bilayer, the overall equilibrium is generally shifted to Meta-I. However, small osmolytes favored the Meta-II state because they can penetrate the protein core, decreasing the osmotic effect on the protein. Furthermore, the metarhodopsin equilibrium was shifted towards the Meta-I state in POPC recombinant membranes compared to the native membrane environment. Analysis of transducin C-terminal peptide-binding isotherms revealed that the G-prottein binding affinity is significantly decreased when the lipid environment is changed from the native lipids to POPC lipids. The POPC lipid membrane has zero spontaneous curvature that shifts the equilibrium towards the more compact, inactive Meta-I state. By contrast, the native lipid membrane environment possesses a negative spontaneous curvature that favors the more expanded state of Meta-II. Our results delineate the crucial role of soft matter in regulating the metarhodopsin equilibrium in a membrane environment." @default.
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• W4225376293 date "2022-05-01" @default.
• W4225376293 modified "2023-10-15" @default.
• W4225376293 title "Modulation of GPCR Rhodopsin Function by Membrane Lipids and Water" @default.
• W4225376293 doi "https://doi.org/10.1096/fasebj.2022.36.s1.r6234" @default.
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