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A computational and mechanistic study of sodium-activated potassium channel function

Project Description

The sodium-activated potassium channel KNa1.1 (KCNT1, Slack, Slo2.2) is found in neurons and its function is to conduct ions across neuronal membranes. Malfunction of this channel causes intellectual disability and severe epilepsy, for which there is no treatment. Additionally, its knockout in mice results in hyperactive pain- and itch-related neurons. It is, therefore, a potential therapeutic target for a range of neurological conditions. Despite its importance in health and disease, many aspects of its function remain poorly understood. Computer simulations provide a powerful tool that enables us to follow the dynamics of proteins and to building dynamic models of membrane proteins in a native milieu. In this study, the student will use molecular dynamics simulations (Kalli group) to study the interplay between ions, water molecules, and the pore-lining side chains of the channel, and to understand in mechanistic detail how this ion channel transitions between active and inactive states. The models derived from these simulations will be evaluated/refined experimentally in the Lippiat and Muench groups by site-directed mutagenesis and electrophysiological measurements. The student will also determine, by cryo-EM, the structure of novel conformations of KNa1.1, such as those caused by disease-causing mutations or drug binding.

Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2019:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference allowance
• Research Costs

At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.
EU candidates require 3 years of UK residency in order to receive full studentship

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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