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.
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