Understanding the structural basis of peptide-activated G protein-coupled receptor signalling to enable drug discovery.

Department / Centre
Biochemistry and Pharmacology
Bio21 Molecular Science and Biotechnology Institute
Primary Supervisor Email Number Webpage
Dr Daniel Scott daniel.scott@florey.edu.au

Summary The Scott group interrogates the molecular mechanisms underlying cellular signalling and exploits these details to develop new tools for drug discovery. A key focus is on G protein-coupled receptors (GPCRs), the largest, yet potentially most underexploited class of drug targets. Our projects combine a wide range of methods such as: protein engineering, directed evolution, cell-based binding and signalling assays, lentivirus, X-ray crystallography, NMR, fluorescence microscopy, electron microscopy, computational modelling, and rational drug design.

Project Details

Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology. In humans, most peptides mediate their actions by binding to cell-surface G protein-coupled receptors (GPCRs), which in response trigger intracellular signalling cascades. Because of the vital roles that peptides play, most of these GPCRs are considered pharmacological drug targets to treat a wide range of diseases. Despite this, only 18% of Class A peptide GPCRs are currently targeted by small molecule drugs, compared to 97% of the aminergic receptor family. This reflects a lack of knowledge about how peptides interact with and activate their cognate GPCRs, which hinders drug development and design. This project focuses on using novel directed evolution methods to engineer peptide GPCRs that preferentially exist in physiologically relevant conformations for which we do not have crystal or cryo-EM structures. The structures of these engineered GPCRs, bound to various peptides, will be investigated using X-ray crystallography, cryo-EM and NMR. Knowledge gained from these projects will contribute to the design of new drugs to treat a range of diseases and conditions such as: dementia, schizophrenia, chronic pain, heart failure, Parkinson's disease, anxiety and depression. Students will be trained in: protein engineering, protein expression and purification, GPCR pharmacological assays, ligand binding assays, protein thermostability measurements, X-ray crystallography, cryo-EM, NMR and peptide modelling and design.

School Research Themes

Cell Signalling

Key Contact

For further information about this research, please contact a supervisor.

Department / Centre

Biochemistry and Pharmacology

Research Node

Bio21 Molecular Science and Biotechnology Institute

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