Engineering G protein-coupled receptors for structural biology and drug discovery with directed evolution.

Department / Centre
Biochemistry and Pharmacology
Bio21 Molecular Science and Biotechnology Institute
Primary Supervisor Email Number Webpage
Dr Daniel Scott

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

G protein-coupled receptors (GPCRs) are a large family of signalling proteins (>800 gene members) located on the surface of all cells in the body, particularly in the brain. GPCR signalling controls virtually every physiological process in the body, making these receptors the targets of many current drugs treating conditions like pain, hypertension, schizophrenia and asthma. GPCRs exist as an ensemble of conformational states (inactive, intermediate and active) in equilibrium, with agonist binding shifting this equilibrium shift towards active states to stimulate cell signalling. A deeper understanding of the structural basis underlying GPCR signalling is needed to guide the design of improved therapeutics.

To do this the major challenges for GPCR structural biology need to be overcome. These include: low expression and purification yields; low protein stability; and the inability to stabilize relevant receptor conformations for analysis. We engineer GPCRs that overcome these issues using in vitro directed evolution methods. Engineered receptors can then be used for crystallography, NMR and other biochemical techniques to further our structural understanding of these proteins and to facilitate structure-based drug design.

This project focuses on developing novel directed evolution methods using lentiviral gene libraries to enable the engineering of GPCRs that preferentially exist in particular, physiologically relevant conformations for which we do not as yet have crystal structures. Such conformationally stabilized receptors will also give us insights into the protein dynamics that control GPCR signalling and provide tools to design new drugs that target and stabilize specific GPCR conformations.

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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