Thème de recherche
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.
- Venkatakrishnan AJ, Deupi X, LEBON G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GFX & Babu MM. Diverse activation pathways in class A GPCRs converge near the G protein-coupling region. Nature. 2016; 536(7617):484-7.
- Magnani F, Serrano-Vega MJ, Shibata Y, Abdul-Hussein S, LEBON G, Miller-Gallacher J, Singhal A, Strege A, Thomas JA, Tate CG. A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies. Nat Protoc. 2016; 11(8):1554-71.
- LEBON G, Edwards PC, Leslie AGW, Tate CG. Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor Mol Pharmacol. 2015; 87(6):907-15.
- Venkatakrishnan AJ, Deupi X, LEBON G, Tate CG, Schertler GF, Babu MM. Molecular signatures of G-protein-coupled receptors. Nature. 2013; 494(7436):185-94.
- 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; 474(7352):521-5.