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Targeting novel molecular mechanisms of family B G-protein-coupled receptors for drug discovery

Secondary Supervisor(s): Dr Giuseppe Deganutti

University of Registration: Coventry University

BBSRC Research Themes:

• Understanding the Rules of Life (Structural Biology,Systems Biology)
• Integrated Understanding of Health (Ageing,Pharmaceuticals)

Project Outline

G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins and play a central role in regulating physiological processes, making them prime targets for drug discovery. However, their structural and functional analysis is hindered by instability when removed from their cell membrane environment. This project uses styrene-maleic acid (SMA) copolymers to encapsulate GPCRs in lipid nanodiscs (SMALPs), preserving their native membrane context and enabling functional studies. The focus is on the calcitonin receptor-like receptor (CLR), a family B GPCR that forms functional complexes with RAMP1, RAMP2, or RAMP3 to generate three distinct GPCRs, namely, calcitonin gene-related peptide (CGRPR), adrenomedullin 1 (AM1R), and adrenomedullin 2 (AM2R) receptors, respectively. These receptors are implicated in neuroinflammation, heart failure, and cancer, making them valuable targets for therapeutic advancement.

The project aims to uncover how RAMPs, and lipids influence CLR pharmacology. Three integrated research strands will be pursued: (1) pharmacological assays using bioluminescence and second messenger assays in engineered mammalian cells; (2) computational modelling to predict CLR conformational changes and lipid interactions; and (3) biophysical analysis of CLR-RAMP complexes in SMALPs using advanced structural techniques.

The student will receive interdisciplinary training in biochemical pharmacology, SMA nanotechnology, biophysics, and molecular dynamics simulations, gaining expertise in both experimental and computational biosciences.

This research supports drug discovery by enabling rational design of CLR-targeting therapeutics and aligns with BBSRC's priorities in healthy ageing, technology development, and data-driven biology. By investigating CLR-RAMP complexes, the project contributes to high-impact bioscience innovation and the development of next-generation medicines.

Regulation of amylin 1 receptor signalling by lipids in obesity and diabetes

Secondary Supervisor(s): Dr Giuseppe Deganutti

University of Registration: Coventry University

BBSRC Research Themes:

• Understanding the Rules of Life (Structural Biology,Systems Biology)
• Integrated Understanding of Health (Ageing,Pharmaceuticals)

Project Outline

The amylin 1 receptor (AMY1R), a G-protein-coupled receptor (GPCR) and member of the calcitonin receptor family, plays a central role in regulating satiety, glycaemic control, and neurovascular function. Its therapeutic relevance in obesity and diabetes is well established, yet the molecular mechanisms underpinning AMY1R activation and signalling remain poorly defined. Recent advances in GPCR biology suggest that membrane lipids actively modulate receptor behaviour, influencing ligand binding, conformational dynamics, and downstream signalling pathways.

This project will investigate how native plasma membrane lipids regulate AMY1R pharmacology, with a focus on metabolic disease contexts. The student will employ an interdisciplinary approach combining lipidomics, bioluminescence-based GPCR functional assays, and computational modelling to elucidate lipid-receptor interactions.

Key objectives include:

- Characterising the lipid environment surrounding AMY1R in physiologically relevant membranes using detergent-free solubilisation techniques (SMA-like polymers) plus mass spectrometry-based lipidomics.

- Assessing how distinct lipid profiles influence ligand binding, G-protein coupling, and intracellular signalling using bespoke nanoBRET-based assays.

- Developing predictive models of lipid-sensitive AMY1R pharmacology through in silico simulations.

By decoding lipid-AMY1R crosstalk, this project aims to inform the design of next-generation therapeutics for obesity and diabetes, aligning with BBSRC's strategic priorities in health, structural biology, and biotechnology.

The student will receive comprehensive training in membrane protein biochemistry, molecular pharmacology, advanced mass spectrometry, and molecular modelling, within a collaborative research group at Coventry University. Opportunities for publication, conference presentation, and industrial engagement will be actively supported.