Structure and dynamics of G protein-coupled receptor–bound ghrelin reveal the critical role of the octanoyl chain

Ferré, Guillaume; Louet, Maxime; Saurel, Olivier; Delort, Bartholomé; Czaplicki, Georges; M’Kadmi, Céline; Damian, Marjorie; Renault, Pedro; Cantel, Sonia; Gavara, Laurent; Demange, Pascal; Marie, Jacky; Fehrentz, Jean‐Alain; Floquet, Nicolas; Milon, Alain; Banères, Jean-Louis

doi:10.1073/pnas.1905105116

Cited by 50 publications

(53 citation statements)

References 40 publications

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“…In fact, amphipols are able to refold protein that has been solubilised by denaturing ionic detergents resulting in stable protein. A number of human GPCRs treated in this way have been shown to maintain ligand binding competency, for example the growth hormone secretagogue receptor (GHSR), CB1 cannabinoid and 5-HT4 serotonin receptors [ 223 , 224 ].…”

Section: Membrane Mimetic Systems For Structural and Functional Stmentioning

confidence: 99%

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

et al. 2020

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Over the past decade, the vast amount of information generated through structural and biophysical studies of GPCRs has provided unprecedented mechanistic insight into the complex signalling behaviour of these receptors. With this recent information surge, it has also become increasingly apparent that in order to reproduce the various effects that lipids and membranes exert on the biological function for these allosteric receptors, in vitro studies of GPCRs need to be conducted under conditions that adequately approximate the native lipid bilayer environment. In the first part of this review, we assess some of the more general effects that a membrane environment exerts on lipid bilayer-embedded proteins such as GPCRs. This is then followed by the consideration of more specific effects, including stoichiometric interactions with specific lipid subtypes. In the final section, we survey a range of different membrane mimetics that are currently used for in vitro studies, with a focus on NMR applications.

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Section: Membrane Mimetic Systems For Structural and Functional Stmentioning

confidence: 99%

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

et al. 2020

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“…AG is the main known high-affinity agonist for the GHSR, while (in physiological concentrations) DAG does not appear to act on the GHSR (Bednarek et al, 2000). A recent study indicates that the octanoyl chain is essential for the pharmacological action of AG and that DAG, while it might bind to the GHSR with very low affinity, is unlikely to stabilize an active GHSR conformation (Ferre et al, 2019). Several binding studies propose the existence of a separate receptor specific for DAG in different tissues and also the brain (e.g., Lear et al, 2010;Togliatto et al, 2010;Fernandez et al, 2016).…”

Section: Ghrelin Receptors (Ghsr)mentioning

confidence: 99%

“…This applies not only for feeding behaviors (Fernandez et al, 2016) but also for stress-related behaviors (Stark et al, 2016). This may be relevant during chronic stress and associated central ghrelin resistance, as AG can be rapidly converted to DAG (De Vriese et al, 2004), which appears to not act via the GHSR (Bednarek et al, 2000;Ferre et al, 2019). Thus, the reported beneficial effects of exogenous AG administration during chronic stress paradigms in rodents may be attributed to DAG rather than AG action.…”

Section: Summary Shortcomings and Future Directions Of Rodent Studiementioning

confidence: 99%

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Fritz

Singewald

Bundel

2020

Front. Synaptic Neurosci.

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Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety-and depression-like behaviors in rodents but some studies suggest that ghrelin may-in contrast-promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stressrelated psychiatric disorders (with a focus on anxiety-and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.

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“…In addition to X-ray diffraction and cryo-electronic microscopy (cryo-EM) [7][8][9][10] , NMR spectroscopy can bring important information regarding conformational and energy landscapes [11][12][13][14][15][16] or, as shown here, on the structure of natural GPCR ligands in their receptor bound-states. This technique can indeed provide a detailed description of the ligand in its bound-state, at physiological temperature and with a native protein [17][18][19][20][21][22][23][24][25] . Especially with very flexible ligands, like those described in this study, NMR data can constitute the basic input to subsequent X-rayor cryo-EM-based molecular modeling of ligand/GPCR complexes.…”

mentioning

confidence: 99%

Structure of the agonist 12–HHT in its BLT2 receptor-bound state

Giusti

Casiraghi

Point

et al. 2020

Sci Rep

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G Protein-Coupled receptors represent the main communicating pathway for signals from the outside to the inside of most of eukaryotic cells. They define the largest family of integral membrane receptors at the surface of the cells and constitute the main target of the current drugs on the market. The low affinity leukotriene receptor BLT2 is a receptor involved in pro-and anti-inflammatory pathways and can be activated by various unsaturated fatty acid compounds. We present here the NMR structure of the agonist 12-HHT in its BLT2-bound state and a model of interaction of the ligand with the receptor based on a conformational homology modeling associated with docking simulations. Put into perspective with the data obtained with leukotriene B4, our results illuminate the ligand selectivity of BLT2 and may help define new molecules to modulate the activity of this receptor.

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Structure and dynamics of G protein-coupled receptor–bound ghrelin reveal the critical role of the octanoyl chain

Cited by 50 publications

References 40 publications

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Structure of the agonist 12–HHT in its BLT2 receptor-bound state

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