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Using a combined computational/experimental approach to understand G protein-coupled receptor activation

Primary Supervisor: Dr John Simms, Life & Health Sciences

Secondary supervisor: Professor David Poyner

PhD project title: Using a combined computational/experimental approach to understand G protein-coupled receptor activation.

University of Registration: Aston University

Project outline:

There is an urgent need to develop new methods of drug discovery against novel targets. Computational biology may offer a new direction for drug discovery and recent advances in the field have resulted in new tools to assist in drug discovery campaigns. However, a major bottle neck in the computational design of drugs is the lack of structural information related to protein dynamics. This is especially true for membrane proteins which are currently the largest class of drug targets but have a limited amount of structural information compared with their soluble protein cousins. A further layer of complexity is also added when the lipid bilayer is taken into consideration. The lipid bilayer not only provides a suitable environment for membrane protein function but individual lipids, which can vary not only between cells but also in disease states, act as allosteric modulators which fine tune the pathways to activation.

The project builds upon a novel computational approach which has identified structural intermediates in the activation of G protein coupled receptors (GPCRs). The method has predicted novel, cryptic binding sites in the intermediate conformations that are not observed in the existing crystallographic structures. The novel binding sites may provide new routes for drug discovery. In addition, investigation of the intermediate structures may also provide predictions of ligand efficacy which is currently unsolved using computational biology.

The aim of this multidisciplinary project is to develop a structural understanding of GPCR activation and will use the human Glucagon Like Protein 1 Receptor (huGLP1R) as a model system. The huGLP1R is currently used as a therapeutic target for the treatment of type 2 diabetes and recent evidence has also implicated its ligands of this protein in neuroprotection against degenerative diseases such as Alzheimer’s. The identification of small molecules which bind to this class of membrane proteins would be of enormous benefit in several areas. This is a multidisciplinary project in which the student will have extensive training in a range of molecular, pharmacological, protein expression and computational techniques to provide a rounded view of an exciting area of drug discovery.

References:

  1. Orellana, L. (2019). Large-Scale Conformational Changes and Protein Function: Breaking the in silico Barrier. Frontiers in Molecular Biosciences. 6.
  2. Simms, J et al (2018). Photoaffinity cross-linking and unnatural amino acid mutagenesis reveal insights into calcitonin gene-related peptide binding to the calcitonin receptor-like

BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology

    Techniques that will be undertaken during the project:

    • Computational Biology (Molecular Dynamics Simulations
    • Ligand docking and Virtual ligand screening)
    • Cell culture
    • Molecular Biology (Gene expression, protein purification, cell proliferation)
    • Intracellular signalling assay development

    Contact: Dr John Simms, Aston University