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Structure-based drug design targeting G-protein-coupled receptors

To achieve GPCR selectivity we need new ways to identify and design more selective GPCR targeting drugs.

Aims

Projects are available that focus on mapping the binding of selective and non-selective ligands to α1A-AR and α1B-AR to guide SBDD and increase our knowledge of the structure and function of α1-ARs.

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 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 family members, causing side effects. 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 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 and to conduct fragment screening to identify novel selective ligands.

Projects are available that focus on mapping the binding of selective and non-selective ligands to α1A-AR and α1B-AR 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. 

Recent Publications: 


1. Bumbak F, Keen AC, Gunn NJ, Gooley PR*, Bathgate RAD* & Scott DJ* (2017) Optimization and 13CH3 methionine labeling of a signaling competent neurotensin receptor 1 variant for NMR studies. BBA Biomembranes 1860: 1372-1383 

2. Yong KJ, Viad T, Shilling, PJ, Fu FJ, Williams LM, DeLuigi M, Plückthun A, Bathgate RAD, Gooley PR & Scott DJ (2018) Determinants of ligand subtype-selectivity at α1A-adrenoceptor revealed using Saturation Transfer Difference (STD) NMR. ACS Chem Biol. 13: 1090–1102 

3. Scott DJ, Kummer L, Egloff P, Bathgate RAD and Plückthun A (2014) Improving the apo-state detergent stability of NTS1 with CHESS for pharmacological and structural studies. Biochim Biophys Acta (BBA)- Biomembranes, 1838: 2817-24 

Scott DJ, Kummer L, Egloff P, Bathgate RAD, Plückthun A. Biochim Biophys Acta (BBA)- Biomembranes, 2014, 1838: 2817-24 
2. Egloff et al, PNAS, 2014, 111:E655-662. 
3. Scott DJ, Plückthun A: J. Mol. Biol. 2013, 425:662-667. 
4. Scott DJ, Kummer L, Tremmel D, Pluckthun A: Curr. Opin. Chem. Biol. 2013, 17:427-435.

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