GPCR-MS · Molecular Details of Membrane Protein Receptor Dynamics
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-08-01 → 2021-07-31
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Molecular Details of Membrane Protein Receptor Dynamics
G protein-coupled receptors (GPCRs) are the proteins responsible for transducing “outside” signals into an intracellular response and their dysfunction is implicated in many diseases. As a result, they are the target of ~40% of drugs on the market. However, many GPCR drugs elicit off-target effects and can produce unwanted effects such as receptor desensitization and/or drug dependence. Currently, the mechanism of action of many GPCR drug targets is poorly understood. GPCRs don’t act in isolation; proteins, metabolites, and lipids, and other molecules all interact synergistically to generate distinct signaling outputs. However, conventional ‘omics’ approaches will never be able to connect the status of critical proteins with metabolites or other effectors since the links between them are broken during sample preparation. It is therefore imperative to maintain molecular interactions to understand the molecular network that contributes to a biological signaling output. This project successfully developed state-of-the-art methods in native mass spectrometry (MS) to interrogate membrane proteins in complex with lipids, ligands, and other molecular interactors intact in the mass spectrometer. By maintaining complexes from the cell to the mass spectrometer, and by dissecting protein-effector interactions in a controlled manner, we are now better equipped to understand mechanisms of membrane protein signal transduction. Specific knowledge of how protein receptors translate “outside” signals into a biological response will change how we approach the treatment of human disease, pain, and other conditions.
Data: CORDIS, © European Union
Project objective
G-protein coupled receptors (GPCRs) are the largest family of membrane proteins. They are involved in transducing stimuli and are implicated in many diseases including cancer and Alzheimer’s disease. As a result, they are the target of ~40% of drugs on the market. Despite an extensive library of known binding partners, dynamics related to GPCR activation (and inactivation) are not fully understood. The proposal uses a hypothesis driven approach to address three interrelated objectives. Objective 1 aims to reveal the propensities for lipids to modulate ligand binding to GPCRs. Objective 2 seeks to understand the intra-molecular factors regulating GPCR and G-protein assembly and their connection with the lipid environment. Objective 3 targets GPCR assembly and binding in the context of a native membrane. This project will use fuse knowledge and tools from molecular biology (e.g. protein expression and mutation) and analytical chemistry (mass spectrometry (MS)) to facilitate a comprehensive understanding of the molecular environment governing GPCR dynamics and assembly. The results of this project will contribute to our understanding of the influence of lipids on conformational dynamics to inform efforts to better understand off-target drug effects and drug tolerance. This information could in turn reveal novel GPCR conformations that facilitate state-selective structure-based drug discovery, with great implications for human health and quality of life.This proposal aligns with goals of the Marie Skłowdowska-Curie Fellowship: I will diversify my professional profile, which has focused on fundamental MS in the US, by gaining new competences in molecular and structural biology in Europe and thereby expand my personal and professional network through international mobility. The host laboratory is at the forefront of MS in structural biology and provides an excellent multidisciplinary training environment.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union