WELCOME
The Institute of Functional Genomics (IGF) is a multidisciplinary research centre which is developing a project focused on the functional genomics of physiological and pathological cellular communications in the fields of neurobiology, endocrinology, oncology and cardiology.
This project is based on a multi-scale strategy from 'molecule to systems' and combines structural, biochemical, genetic, epigenetic, omics, physiological and behavioural studies. A major effort is paid to the development of single-cell studies through multiple dimensions and multi-omic approaches, that are necessary to address the complexity of life.
The project of IGF is increasingly based on translational research, promoted by the recruitment of teams of clinicians from different fields (neurovascular, diabetology, neuro-oncology and psychiatry). The objective is to identify new mechanisms and concepts in the field of cellular communications, in order to develop new therapeutic strategies and diagnostic tools.
STRUCTURE OF THE ADENOSINE A2A RECEPTOR BOUND TO AN ENGINEERED G PROTEIN
G protein-coupled receptors (GPCRs) activate intracellular signalling proteins (G proteins and arrestins) in response to extracellular signalling molecules. GPCRs are highly dynamic proteins, which rapidly interchange between different conformational states. In order to understand the molecular mechanisms of GPCR activation, and to facilitate efficient drug design, structures of GPCRs in all conformational states are required. Unsurprisingly, ternary complexes, involving native signalling proteins, have proved most difficult to crystallise due to their instability. We have developed an engineered G protein, which is significantly more stable in complex with GPCRs than native Gs. Engineered Gs is particularly stable in short chain detergents and thus suitable for crystallisation of GPCR – G protein complexes by vapour diffusion. Additional components, such as nanobodies, are not required for maximal stability. We have purified complexes of engineered Gs with both the adenosine A2a receptor (A2aR) and β1-adrenergic receptor (β 1AR) and have determined the structure of wild type human A2aR bound to engineered Gs at 3.4 Å resolution by X ray crystallography. The structure will be presented, compared to the β2-adrenergic receptor-Gs complex and implications for GPCR signalling discussed.
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