MECHANICAL ALLOSTERY OF THE LIPID BILAYER ON GPCR ACTIVATION

Mechanotransduction plays a role in countless cellular signals. It forms the basis of sensory abilities, the shaping of developing tissues during embryogenesis, breathing, blood pressure, etc. At the physiological level, biological membranes represent a mechanosensing structure. This enables cells to regulate their functions in response to mechanical stimuli. As essential mediators between the interior of cells and their external environment, MPs play a central role in mechanotransduction in health and disease. G Protein-Coupled Receptors (GPCRs) represent the largest family of membrane receptors with more than 800 members expressed in humans. They play a major role in eukaryotic cellular signaling and, as such, are an important drug target, as over one-third of Food and Drug Administration (FDA)-approved drugs target this family of receptors. Besides ionotropic receptors, several recent findings point toward the mechanosensitivity of metabotropic GPCRs in the regulation of immune, vascular, cardiac, and nervous system with pathophysiological consequences.

 

       We propose to provide an unprecedented molecular understanding of how mechanical perturbations of the lipid bilayer impact the conformational landscape of mechanosensitive GPCRs. We will investigate the energy landscape and signaling of GPCRs in response to variations in mechanical properties, such as membrane fluidity and tension. Our primary goal is to decipher the link between the sensor and transducer functions of these GPCRs when exposed to mechanical stimuli. We aim to distinguish between chemical and mechanical stimuli in the activation of GPCRs and, if applicable, establish a connection between the two.

 

       We will consider here the Growth Hormone Secretagogue (GHSR) and the Adenosine A_2A (A_2AR) receptors as class A GPCR models. GHSR binds the peptide hormone ghrelin and plays a key role in regulating food intake, energy expenditure and addictive behaviors, among other functions. A_2AR, on the other hand, modulates a wide range of physiological responses throughout the human body, making it a highly valuable drug target in the treatment of neurodegenerative diseases and cancer immunotherapy.

 

       During the PhD, the PhD student will prepare isotopically labelled GPCRs in nanodiscs of various lipid composition and characterize the impact of the lipid composition, ligand binding and temperature/hydrostatic pressure on the GPCR conformational landscape by simple and sophisticated NMR experiments.

 

       This PhD project will be jointly supervised by Laurent Catoire (IBPC, Paris) and Ewen Lescop (ICSN, Gif/Yvette) and also benefits from close and long-standing collaborations with pharmacology/ fluorescence spectroscopy (JL Banères, Montpellier) and molecular modelling (J. Hénin, G Stirnemann, Paris). Hence, the complementary techniques will help us better understand how the mechanical properties of the lipid bilayer impact the activation of GPCRs at the molecular and atomic scale in conjunction with in cellulo signaling measurements. Biochemistry will be carried out at IBPC Paris, and NMR will be carried out at ICSN Gif/Yvette.

 

 

Recent bibliography from this collaboration network :

- Fourel et al. (2025) Allosteric coupling between a lipid bilayer and a membrane protein. Biophysical Journal, 124, 2613–2626

- Pozza et al. (2022) Exploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure. Nature Communications, 13, 1780.

No particular funding (self-financing, teaching hours, teaching fellowship)

The chosen candidate will be trained to go through the selection process of our doctoral school. We are waiting for the evaluation of an ANR grant with potential PhD funding.

The PhD student will be supervised at ICSN by Ewen Lescop (icsn.cnrs.fr/cv/lescop) and at IBPC by Laurent Catoire (co-director of the thesis, http://umr7099.ibpc.fr/research-themes/molecular-signalisation-pathway-of-gpgrs/) and will benefit from the support of other members of the teams on biochemical, NMR and structural biology aspects.

With a staff of nearly 140 people, ICSN (http://icsn.cnrs.fr) is the chemistry centre of the CNRS campus in Gif sur Yvette, 30 km south of Paris by train RER B. The Institute is located on the edge of the Paris-Saclay campus, which brings together nearly 15% of French research, and is an integral part of this new University. ICSN develops activities at the chemistry-biology interface, with natural substances as the object of study and main source of inspiration. ICSN is organised in four research departments and has important analytical platforms. The PhD thesis will be carried out within the NMR - Structural Biology and Chemistry team that is responsible for a high field NMR facility that is part of the national infrastructures Infranalytics and Frisbi.

IBPC (http://umr7099.ibpc.fr/) is a laboratory located in the centre of Paris that brings together biologists, physicists and chemists who are interested in the structure, structural dynamics and physical chemistry of membrane proteins, either in membrane mimetic systems (liposomes or nanodiscs), or in classical detergent solutions or alternative surfactants such as amphipols. Following in the footsteps of Jean Perrin, who created the institute with Baron Edmond de Rothschild, IBPC develops interdisciplinary fundamental research for health and environment. The PhD student will benefit from the extensive experience of the team "Molecular Signalisation Pathway of GPGRs".

Université Paris-Saclay

The candidate should ideally have a background in biochemistry, chemistry, physical chemistry, biophysics, molecular biology and/or structural biology or a related discipline and a strong interest in structure-dynamics-interaction-function studies of proteins/lipids and a sensitivity to the physical chemistry of biological systems. Experience in protein expression and purification, and in NMR spectroscopy will be a plus.