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GPCR conformations

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Structural studies of ligand induced conformational changes in G protein coupled...

Structural studies of ligand induced conformational changes in G protein coupled receptors G protein-coupled receptors (GPCRs) are eukaryotic seven-alpha-helix transmembrane proteins which are involved in extracellular signal transduction across the cellular membrane. Aim of the proposed research is to structurally cha... ver más

31/05/2013

PSI

178K€

Presupuesto del proyecto: 178K€

Líder del proyecto

PAUL SCHERRER INSTITUT No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2013-05-31 No tenemos la información de la convocatoria

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Líder del proyecto

PAUL SCHERRER INSTITUT No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 178K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto G protein-coupled receptors (GPCRs) are eukaryotic seven-alpha-helix transmembrane proteins which are involved in extracellular signal transduction across the cellular membrane. Aim of the proposed research is to structurally characterise ligand-induced conformational changes in GPCRs, to identify the number of alternative conformations the GPCR can adopt, and to engineer conformationally stabilised GPCR variants for subsequent biophysical and crystallographic studies. The research will focus on cannabinoid receptor type 2 and beta-1 adrenergic receptor. Both GPCRs can be expressed and purified from recombinant Escherichia coli as well as insect and mammalian cells. Degree of ligand-induce conformational change will be determined for each amino acid residue by using a novel protein-engineering approach that combines alanine scanning mutagenesis and conformational phi-value analysis. Transition temperatures of denaturation for native and each mutated protein will be determined in presence and absence of particular ligand by high-throughput differential scanning fluorimetry or radioligand-binding assays. These results will be used in engineering of GPCR mutants that are more stable and locked in the specific (eg, activated or inactive) conformational state. Ligand-binding to the stabilised mutants and their functionality will be monitored by fluorescence anisotropy titrations, as well as by radioactive assays using the corresponding G proteins. The stable and functional variants will be used in crystallisation trials. The diffraction data from the expected microcrystals will be collected on the microfocus X-ray beamline. Crystal structures will be determined by molecular replacement. The proposed research will give insights into the activation mechanisms of GPCRs. Detailed understanding of the conformational changes accompanying receptor activation is a prerequisite for rational design of therapeutic drugs affecting GPCRs.

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