Thèse Allostérie Mécanique des Bicouches Lipidiques sur l'Activation des Rcpgs H/F - 75

Établissement : Université Paris-Saclay GS Santé et médicaments
École doctorale : Innovation thérapeutique : du fondamental à l'appliqué
Laboratoire de recherche : Institut de Chimie des Substances Naturelles
Direction de la thèse : Ewen LESCOP ORCID 0000000226239365
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-10-01T23:59:59Ce projet de doctorat vise à explorer l'impact de diverses propriétés mécaniques de la bicouche lipidique, telles que la fluidité ou la tension, sur l'activation des récepteurs couplés aux protéines G (RCPG) à l'aide de techniques hautement complémentaires, notamment la biochimie de pointe et la RMN, à l'interface avec la pharmacologie moléculaire et des simulations de dynamique moléculaire. Une meilleure compréhension de la relation intime entre ces protéines et la mécanique membranaire contribuera à terme au développement de composés thérapeutiques plus efficaces.

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 A2A (A2AR) 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. A2AR, 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, and NMR will be carried out at Gif/Yvette.