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Unfolding the GLP-1R palmitoylation mechanism for better diabetes therapies

Secondary Supervisor(s): Professor Jennifer Greaves

University of Registration: Coventry University

BBSRC Research Themes:

• Understanding the Rules of Life (Structural Biology)
• Integrated Understanding of Health (Diet and Health)

Project Outline

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that plays a central role in glucose regulation and is a major target in type 2 diabetes and obesity treatments (the blockbuster drug Ozempic, for example). One important but less understood aspect of GLP-1R regulation is palmitoylation, a reversible lipid modification where a fatty acid (commonly palmitate) is attached to specific cysteine residues on the receptor. This modification can influence receptor localisation, stability, signalling, and interaction with other proteins. Despite the tremendous importance of GLP-1R as a drug target, almost nothing is known about the enzyme responsible for its palmitoylation (S-acylases and deacylases). This project aims to uncover how GLP-1R palmitoylation happens and its effects on receptor structure and function, combining molecular dynamics (MD) simulations with wet-lab validation.

The research will focus on three areas:

1) Identify specific S-acylases and deacylases involved in GLP-1R palmitoylation and understand the structural interactions involving GLP-1R

2) Use MD simulations to model GLP-1R in both palmitoylated and non-palmitoylated states. This will help us understand how palmitoylation alters receptor flexibility, membrane anchoring, and interactions with signalling partners.

3) Cell-based assays and techniques such as click chemistry, signalling assays, and confocal microscopy will be used to study GLP-1R receptor localisation, stability, and activity upon palmitoylation.

Impact: Understanding palmitoylation could reveal new ways to fine-tune GLP-1R activity, potentially leading to improved therapies for metabolic diseases. The project also provides valuable training in computational biology and molecular pharmacology, skills highly relevant to academic and industry careers in drug discovery.

Tuning G protein-coupled receptor pharmacology with a novel drug design approach

Secondary Supervisor(s): Dr Hoor Ayub

University of Registration: Coventry University

BBSRC Research Themes:

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

Project Outline

The pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1R) and the parathyroid hormone-1 receptor (PTH1R) are class B G protein-coupled receptors (GPCRs) involved in conditions such as depression, post-traumatic stress disorder, chronic pain, migraine, and osteoporosis. Despite their therapeutic relevance, few non-peptide agonists exist for these receptors. PCO371 (Kobayashi, K. et al. Nature 618, 1085-1093 (2023)) is a recently discovered small molecule that activates multiple class B GPCRs through a novel intracellular mechanism. However, it lacks selectivity between PAC1R and PTH1R due to their structural similarity, limiting its usefulness as a drug lead.

This project aims to design selective PCO371-like agonists by exploring receptor flexibility and water-mediated interactions. Water molecules play a key role in GPCR activation and can influence ligand binding.

The research will focus on three areas:

(1) identifying transient, receptor-specific sub-pockets to improve selective binding

(2) analysing differences in water molecule behaviour within the binding site to enhance receptor-specific interactions

(3) understanding the binding pathway of PCO371 to design faster, more selective analogues.

The PhD student will gain expertise in computational drug design and experimental pharmacology. Techniques include molecular modelling, virtual screening, and molecular dynamics simulations, alongside live-cell assays using engineered mammalian cells expressing PAC1R and PTH1R. Site-directed mutagenesis will be used to validate computational findings.

The long-term goal is to develop orally available drugs targeting PAC1R and PTH1R, improving treatment options and patient compliance. The approach is also applicable to other class B GPCRs, potentially broadening its impact across multiple therapeutic areas.

Designing Long-Awaited PAC1 Receptor Antagonists

Secondary Supervisor(s): Dr Hoor Ayub

University of Registration: Coventry University

BBSRC Research Themes:

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

Project Outline

The pituitary adenylate cyclase-activating polypeptide (PACAP) at its receptor, PAC1, has been implicated in a variety of physiological contexts relevant to human health and disease, such as depression, posttraumatic stress disorder, migraines, nerve pain, and stroke. Blocking PAC1 activity could help treat these disorders, but current drugs and tool compounds are limited, often peptide-based, and lack specificity. This project aims to design both peptide and small, drug-like molecules that can selectively block PAC1, using a combination of computational and experimental approaches. Developing selective PAC1 antagonists could lead to new oral treatments for neurological and inflammatory conditions. The approach is also applicable to other related receptors, potentially broadening its impact across multiple therapeutic areas.

The research will focus on three areas:

1) Use molecular dynamics (MD) simulations to study how PAC1 behaves at the atomic level. These simulations will help identify flexible regions and hidden binding pockets that could be targeted by new molecules.

2): Design and virtually screen small molecules that fit into these pockets and block PAC1. Promising candidates will be selected based on their predicted binding strength and specificity.

3): Test selected molecules in live mammalian cells engineered to express PAC1. Using receptor activity assays, we'll evaluate how well these molecules block PAC1 signalling and confirm their effectiveness.

This project offers hands-on experience in both computational drug design and wet-lab pharmacology. You will learn advanced modelling techniques, virtual screening, and cell-based assays, skills highly relevant to pharmaceutical research.