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Allosteric modulation of G-protein Coupled Receptors conformational landscape

Objective

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors in eukaryotes. They bind a wide range of ligands, such as neurotransmitters, hormones, lipids and many others. GPCRs are the target of more than 30% of the drugs currently on the market, addressing neuropsychiatric, cardiovascular, pulmonary and metabolic disorders, cancer, obesity and AIDS.
The functional versatility of GPCRs cannot be explained by a simple two-state model of activation considering only an active and an inactive state, as these receptors are highly dynamic and can explore a wide range of conformations.
Some receptors of the family can signal in the absence of ligand (basal activity), and despite GPCR have been largely studied in the past years, little is known about their signal transduction mechanism.
Apart from ligands and signalling partners, the structure and function of GPCRs can be modulated by lipids.
In this context, our research will be divided in two steps: delineating the role of lipids on GPCR conformational landscape at the molecular scale (Aim1) and exploring an additional allosteric factor in line with lipid composition, the homo- and hetero-receptor oligomerisation (Aim2).
To that purpose, we will apply an integrated, multidisciplinary analysis, to characterize protein dynamics under physiological conditions, with the GPCR reconstituted in model lipid systems or living cells, and in the presence of ligands, signalling and regulatory partners. We will use conformational probes to investigate the effect of lipids and other GPCRs on receptor dynamics, and correlate these findings with functional properties such as agonist binding and G protein coupling.

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Topic(s)

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Funding Scheme

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MSCA-IF-GF - Global Fellowships

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2017

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Coordinator

UNIVERSITE DE MONTPELLIER
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 246 668,40
Address
163 RUE AUGUSTE BROUSSONNET
34090 Montpellier
France

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Region
Occitanie Languedoc-Roussillon Hérault
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 246 668,40

Partners (1)

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