How to design a better GPCR drug: understanding the structural basis of ligand selectivity at α1-adrenoceptors.
- Department / Centre
- Biochemistry and Pharmacology
- Bio21 Molecular Science and Biotechnology Institute
|Dr Daniel Scottfirstname.lastname@example.org|
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.
Most G protein-coupled receptors (GPCRs) are activated though extracellular interactions of natural ligands, such as hormones or neurotransmitters, to the GPCR's ligand binding site. Binding induces a conformational change of the GPCR resulting in the transmission of intracellular signals. The GPCR gene super-family is made up of numerous sub-families that are all activated by the same ligands, but often control different physiological processes. This presents a challenge for drug discovery because synthetic compounds that are identified to bind to the natural receptor binding site will often bind to similar sites on other receptor family members (off targets), causing side effects and unwanted physiological responses. To achieve GPCR selectivity we need new ways to identify and design more selective GPCR targeting drugs. To meet this challenge we need to understand how natural ligands, and drug candidates, bind to receptors at the atomic level. Contemporary structure-based drug design (SBDD) uses atomic resolution methods (X-ray, NMR and Molecular Dynamics) coupled with high-throughput screening (NMR, Surface Plasmon Resonance, Isothermal Titration Calorimetry, and Microscale Thermophoresis) of small fragment molecules to discover novel leads. A huge challenge for GPCRs is that they are very unstable and "fall apart" during the experiments needed to guide SBDD. We have engineered stabilized variants of two closely related GPCR subtypes, the α1A- and α1B-adrenoceptors (α1A-AR and α1B-AR). The stability of these receptors in the purified state has allowed us to probe the binding of non-selective and selective ligands with NMR to further our understanding of the structural basis of ligand selectivity. Projects are available focuses on mapping the binding of selective and non-selective ligands to α1A-AR and α1B-AR with these methods to guide SBDD and increase our knowledge of the structure and function of α1-ARs. Designed, selective α1-AR ligands will be critical tools for understanding the precise roles of these receptors in the body and could be candidates for treating heart disease, epilepsy and neurodegenerative diseases.
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Research NodeBio21 Molecular Science and Biotechnology Institute
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