STRUCTURAL BIOLOGY OF G PROTEIN COUPLED RECEPTORS: A FOCUS ON CLASS C
Department: Neurosciences - Research axis: GPCR signaling

Research subject

We are aiming to determine high-resolution structure of G protein-coupled receptors (GPCRs) bound to their ligands and to their signalling complexes.

GPCRs are membrane proteins and are localised at the plasma membrane of eukaryotic cells. They mediate information for broad variety of stimuli such as photons, hormones, neurotransmitters, odorants, and are crucial for the cell communication by transducing extracellular signal to the intracellular compartment of the cells. They are classified into three main classes, A, B and C. Class C GPCRs are represented by the receptors for the two major neurotransmitters glutamate and GABA, by the receptors for Ca2+, and by sweet and umami taste receptors. The pivotal role of class C GPCRs in intercellular communication makes them important targets for the development of drugs for the treatment of disorders such as anxiety, drug abuse, schizophrenia, Parkinson’s disease, and Fragile X syndrome. We will investigate the 3D structure of purified GPCRs using X-ray crystallography, with a focus on class C GPCRs. In the following step, we will study the structure of class C GPCRs signaling complexes, including class C GPCRs bound to their cognate G protein. It is also now well known that GPCRs, including class C GPCRs, activate a range of additional signalling pathways by interacting with arrestins, kinases and other partners, in a ligand-specific manner. The structure determination of those complexes will be required to fully understand the activation mechanism of Class C GPCRs by their endogenous ligand and others newly developed drugs. By Combining structural biology and molecular pharmacology tools, will be able to understand, at the molecular level, the activation mechanism of this important family of receptor.

 

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Link to team web site

Team

Team leader

Guillaume Lebon
CRCN, CNRS


  IGF Nord 224b

  04 34 35 93 30

 

Staff

Gaëtan Bellot
CRCN, Inserm


  IGF Nord 210a

  04 34 35 92 64

 

Allan Mills
Post-doctorant(e), Inserm


  IGF Nord 213

  04 34 35 93 30

 

Chady Nasrallah
Post-doctorant(e), UM


  IGF Nord 212a

  04 34 35 93 30

 


Major publications

  • Molecular signatures of G-protein-coupled receptors. Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM. Nature. 2013 Feb 14;494(7436):185-94. doi: 10.1038/nature11896.
  • Lebon G, Warne T & Tate C.G. Agonist-bound structures of G protein-coupled receptors. Curr Opin Struct Biol. 2012, DOI 10.1016/j.sbi.2012.03.007.
  • Lebon G, Warne T, Edwards PC, Bennett K, Langmead CJ, Leslie AG, Tate CG. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature. 2011, 2011 May 18;474(7352):521-5 .
  • Lebon G, Bennett K, Jazayeri A, Tate CG. (2011) Thermostabilisation of an Agonist –bound Conformation of the Human A2A Receptor. J Mol Biol. 2011 Jun 10; 409(3):298-310.
  • Lebon G, Langmead CJ, Tehan BG, Hulme EC. (2009) Mutagenic mapping suggests a novel binding mode for selective agonists of M1 muscarinic acetylcholine receptors. Mol Pharmacol. 2009 Feb; 75(2):331-41

 

 

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