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Structural studies of mammalian Cys-loop receptors

Objective

In the brain, Cys-loop receptors mediate fast neurotransmission. They function as allosteric signal transducers across the plasma membrane: upon binding of one or more neurotransmitter molecules to an extracellular site, the receptors undergo complex conformational transitions that result in transient opening of an intrinsic ion channel. The Cys-loop family comprises receptors activated by serotonin, acetylcholine, glycine and GABA. Mammalian receptors are also the targets of a legion of psycho-active and therapeutic compounds (including nicotine, benzodiazepines, anti-emetics, general anaesthetics). Our structural knowledge is currently limited to invertebrate homologues. Atomic structures mammalian receptors are therefore acutely missing in order to understand their physiological role in molecular terms, and to be able to develop new drugs targeting them.

The project proposes to decipher the operation mechanism, the pharmacology and conformational transitions of mammalian Cys-loop receptors. Starting with a solid body of preliminary results, we will obtain new high-resolution structures, taking advantage of antibody-based crystallization chaperones. We will try and record for the first time a ‘molecular movie’ of the gating conformational transition in cristallo. On the way, we will also investigate the potential of antibody-based modulators of Cys-loop receptors for biomedical applications.

The applicant has solved in the past the structures of a bacterial Cys-loop receptor and of the mouse serotonin receptor. The proposed research will take place at the CNRS in Grenoble, France, in a very favourable environment for structural biology.

Fields of science (EuroSciVoc)

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Programme(s)

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Topic(s)

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Funding Scheme

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ERC-STG - Starting Grant

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Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

(opens in new window) ERC-2014-STG

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Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
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.

€ 1 437 000,00
Address
RUE MICHEL ANGE 3
75794 PARIS
France

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Region
Ile-de-France Ile-de-France Hauts-de-Seine
Activity type
Research Organisations
Links
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.

€ 1 500 000,00

Beneficiaries (2)

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