Quick Project Snapshot
Designing allosteric modulators of the neurotensin receptor 1 (NTS1) as potential drugs for schizophrenia
Neurotensin (NT) is a 13-residue peptide expressed in the central nervous (CNS) gastro-intestinal and cardiovascular systems. NT acts as a neuromodulator of classical neurotransmitters such as dopamine and glutamate in the mammalian CNS by activating the G protein-coupled receptor (GPCR) NTS1. Preclinical studies have demonstrated a remarkable similarity between the behavioural effects of centrally administered NT and peripherally administered antipsychotics. Brain NT concentrations are increased following antipsychotic treatment and untreated schizophrenia patients have been shown to have low cerebrospinal levels of NT. Thus NTS1 agonists, or positive allosteric modulators to enhance endogenous NT signalling, are considered to have potential for the treatment of schizophrenia, which affects approximately 1% of the US and Australian populations. Using our engineered NTS1 proteins, we have identified an allosteric binding site in NTS1 which plays an important role in receptor activation by NT. Using structure based drug design, ligands that bind to this allosteric site will be conceived and tested for allosteric activity on NTS1 expressing cells. Students will be trained in techniques including protein structure analysis, computational ligand docking, protein expression and purification, robotic ligand binding assays, cell-based GPCR assays, nuclear magnetic resonance spectroscopy and pharmacological analysis. Ultimately, allosteric modulators of NTS1 may prove to be drug candidates for treating schizophrenia.
- Scott, D. J., Kummer, L., Egloff, P., Bathgate, R. A. & Pluckthun, A. Improving the apo-state detergent stability of NTS with CHESS for pharmacological and structural studies. Biochim Biophys Acta, In Press, (2014).
- Egloff, P., Hillenbrand, M., Klenk, C., Batyuk, A., Heine, P., Balada, S., Schlinkmann, K. M., Scott, D. J., Schutz, M. & Pluckthun, A. Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli. Proc Natl Acad Sci U S A 111, E655-662, (2014).
- Yong, K. & Scott, D. J. Engineering Stabilised G Protein-coupled Receptors for Biochemical and Structural Studies, in Australian Biochemist Vol. 44 (2013).
- Scott DJ, Kummer L, Tremmel D, Plückthun A, Stabilizing membrane proteins through protein engineering, Current Opinion in Chemical Biology, 17, 427-435.
- Scott DJ, Plückthun A, Direct molecular evolution of detergent stable G protein-coupled receptors using polymer encapsulated cells, Journal of Molecular Biology, 2013 Feb; 425(3):662-667.
Receptor Structure and Drug Discovery Laboratory
Protein instability poses a major barrier to the characterisation and deployment of many proteins into industrial and biotechnological applications. Membrane proteins are a class of proteins that are particularly unstable, yet are highly important as they are the main targets for most prescription drugs. Membrane proteins are located on the surface of all types of cells and are involved in processes such as sensing neurotransmitters, driving neural impulses and responding to drug treatment. The instability of membrane proteins, however, makes them difficult to study. We use novel technology (CHESS) to engineer stabilised membrane proteins, particularly neuropeptide-binding G protein-coupled receptors (GPCRs), to aid in elucidating the atomic level mechanisms that govern their function and to facilitate novel drug discovery.
A particular focus of the laboratory is engineering members of the relaxin receptor family to enable greater understanding of how these receptors work at the molecular level and in turn enable the design of drugs targeting these important receptors. We also use this technology to engineer highly stable versions of other protein classes, such as fluorescent proteins and enzymes, for biotechnological and industrial applications.
All Projects by this LabEnabling technologies for structure based drug design at G protein coupled receptorsDesigning allosteric modulators of the neurotensin receptor 1 (NTS1) as potential drugs for schizophreniaDrug discovery targeting α1-adrenoceptors (α1-ARs)
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.