Diploma Worker, AstraZeneca Gothenburg, 30 hp

Title:

Structural analysis of ß-Arrestin signalling at a GPCR.

Aug 28, 2017 - Jan 14, 2018

Project description:

Abstract for Master Thesis student

G-protein coupled receptors (GPCRs), signal transducers that process extracellular stimuli to initiate an intracellular response, are important targets in drug discovery.

The GPCR superfamily is characterised by its signature seven transmembrane domain structure, with an extracellular N-terminus and an intracellular C-terminus.

GPCRs are activated by a wide variety of ligands and early evidence suggests a universal mechanism of activation for all receptors through the association of G proteins to produce a functional response and ß-arrestins to initiate the desensitisation process and stop the response.

More recently it has been found that the ß-arrestin pathway can also produce a response of its own through G protein-independent signalling. Since then the concept of functional selectivity or biased agonism has been observed which proposes that a ligand binding to a GPCR can differentially activate the G protein or ß-arrestin pathways by stabilising different receptor conformations.

The aim of this project is to identify the key amino acid residues within the receptor which are necessary for activation of the ß-arrestin pathway and map the receptor conformation required for ß-arrestin activation. This project will involve the development of different cell lines by transfiently transfecting plasmids containing the receptor with different amino acid mutations into a DiscoverX PathHunter parental cell line. These receptors will then be screened using the DiscoverX PathHunter assay platform to monitor ß-arrestin recruitment. This is an experimental project, however once data has been generated there will be an opportunity to work with computational chemists, and using the crystal structure of the receptor understand how these amino acids are involved in activation.

Last date to submit your application is April 15th.

For questions, please contact Fredrik Wågberg at AstraZeneca.

Email: fredrik.wagberg@astrazeneca.com.