About the Project
Solute carriers (SLCs) are the second largest class of membrane-embedded proteins with over 400 members organised into 66 families. SLCs are essential for catalysing the efficient transport across biological membranes of a wide range of compounds such as sugars, lipids, amino acids, nucleotides, and other metabolites. Whilst most SLCs are directly implicated in many diseases, they remain largely underexplored primarily due to the challenges they pose to study these complexes in their native environments. Another important class of membrane proteins is the G-Protein-Coupled Receptors (GPCRs). GPCRs are responsible for many pathological conditions, and constitute the targets of more than half of known drugs. Despite their importance, existing methods often fail to uncover information about the structural dynamics of GPCRs, precluding advances related to therapeutic interventions and drug discovery.
Mass spectrometry (MS) has emerged as an extremely valuable tool for characterizing important membrane proteins and their complexes. Here, we aim to develop a novel MS-based platform that brings together cyclic hydrogen deuterium exchange (HDX)-MS with ion mobility (IM)-MS, native MS and EPR Spectroscopy. By leveraging the synergetic information of all methods to target SLCs and GPCRs, it will allow overcoming current limitations in chromatographic separations and capture their structural dynamics at unsurpassed level of resolution. A key aim of our approach is to obtain this information closer to their native environment. This will allow exploring currently unknown mechanisms that govern the function of SLCs such as allosteric effects and intrinsic dynamics in response to substrate and lipid binding.
The development of our MS-based platform will unlock the SLC/GPCR family and allow novel drugs to be discovered against this important target class. In addition, we are exemplifying this potential using the potassium chloride cotransporter 2 (KCC2). KCC2 is a K-Cl transporter that is responsible for transporting Cl- (as a Cl- K+ pair) out of neurons. It works together with the Na++ Cl− co-transporter 1 (NKCC1) which imports Cl- into neurons, and the KCC2/NKCC1 ratio ultimately regulates chloride homeostasis.
Reduced cell surface expression of WT KCC2 has been found to increase seizure susceptibility in mice models (kainate-induced epilepsy) (1). Several human mutations that either reduce the Cl- extrusion activity of KCC2 or the cell surface expression of KCC2 have been linked to patients with epilepsy (2). KCC2 therefore represents an attractive target for the therapeutic intervention of epilepsy, where compounds which positively modulate the activity of the carrier will restore chloride homeostasis. To date, no clinically developed drugs of solute carrier targets are positive allosteric modulators and therefore represent a challenge to the drug discovery industry. A significant hurdle is the need to perform compound screening with the transporter in its active, outward-open state – therefore allowing compounds which stabilise this conformation to be identified. HDX represents a potentially disruptive approach for these applications, since conditions can be optimised which increase the population of the therapeutically relevant conformation ahead of screening, currently not possible using traditional tools.
Eligibility
Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form you must select MRC DTP PhD Programme. If you select the incorrect programme your application cannot be considered. Full details on how to apply can be found on the MRC DTP website.
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application, please contact our admissions team.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website.
Funding Notes
This is a 4 year CASE studentship in partnership OMass Therapeutics. This covers tuition fees and an annual stipend. This does not include any costs associated with relocation.
References
2. Martin Puskarjov, Patricia Seja, Sarah E Heron, Tristiana C Williams, Faraz Ahmad, Xenia Iona, Karen L Oliver, Bronwyn E Grinton, Laszlo Vutskits, Ingrid E Scheffer , Steven Petrou, Peter Blaesse , Leanne M Dibbens , Samuel F Berkovic , and Kaila, A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Reports, 15(6), 723-9, 2014.
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