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Dr J D Lippiat
Prof Stephen Muench
Dr Antreas Kalli
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
The sodium-activated potassium channel KNa1.1 (KCNT1, Slack, Slo2.2) is found in neurons and couples sodium influx to excitability. Dysfunction of this channel causes intellectual disability and severe epilepsy, for which there is no treatment, making it 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. The aim of this project is to develop a molecular understanding of how sodium ions bind to the protein, and how this causes conformational changes, that result in channel opening. Structural approaches involving cryo-EM and molecular dynamics simulations will be used to identify intermediate structural conformations. The structural models developed will be evaluated/refined experimentally by site-directed mutagenesis, electrophysiological measurements, and by identifying state-specific ligands.
Funding Notes
Applicants will need to have identified and/or secured a source of funding for tuition fees, research and living costs.
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Career overview
Dr Jonathan Lippiat joined the University of Leeds in 2004. He obtained his PhD in Cell Physiology and Pharmacology from the University of Leicester in 2001. Following this, he undertook postdoctoral research at the University of Oxford, where he was elected a Junior Research Fellow at Linacre College in 2002. Dr Lippiat''s research interests encompass ion channel properties, structure, and pharmacology, with a primary focus on potassium channels, as well as calcium channels, chloride channels, and transporters. His current research centres on the KNa1.1 sodium-activated potassium channel and KCNT1-related epilepsy, employing cryo-EM structures for virtual high throughput screening to identify novel inhibitors of the channel and to understand how mutations affect channel activity. Dr Lippiat collaborates with structural biologists, medicinal chemists, and neuroscience researchers, and is involved in projects related to host cell ion channels in viral infection and replication. He leads a research group and serves as a Programme Leader for Human Physiology undergraduate degrees.
Research interests
Dr Lippiat''s research encompasses a broad range of interests in ion channel properties, structure, and pharmacology, with a primary focus on potassium channels. He also investigates calcium channels, chloride channels, and transporters, particularly those implicated in human disorders or that can be targeted by potential therapeutics. His current main area of research involves the KNa1.1 sodium-activated potassium channel and KCNT1-related epilepsy, utilising cryo-EM structures of the channel for virtual high throughput screening to identify novel inhibitors and to understand how mutations affect channel activity. Dr Lippiat''s projects are interdisciplinary, collaborating with structural biologists, medicinal chemists, and neuroscience researchers, as well as virology researchers on projects involving host cell ion channels in viral infection and replication. Current research projects include the identification and characterisation of ion channel-binding Affimer proteins, structural studies of human ion channels, potassium channel pharmacology, structure-based drug discovery, and genome editing of human cells with patient-specific mutations. Techniques employed in his research include patch clamp electrophysiology, fluorescence imaging, gene cloning, and structure-based virtual screening.
Ion Channels
Electrophysiology
Pharmacology
Potassium Channels
Calcium Channels
Chloride Channels
Transporters
KNa1.1 Sodium-Activated Potassium Channel
KCNT1-Related Epilepsy
Cryo-EM
Virtual High Throughput Screening
Ion Channel-Binding Affimer Proteins
Structural Studies
Potassium Channel Pharmacology
Structure-Based Drug Discovery
Genome Editing
CLC-5 Function
Dent''s Disease
Endocytosis
Interdisciplinary Research
Neuroscience
Virology
Patch Clamp Electrophysiology
Fluorescence Imaging
Gene Cloning
Mutagenesis
Mammalian Cell Expression.
Career overview
Dr Stephen Muench studied for an undergraduate degree in Biochemistry and Microbiology at the University of Sheffield in 1997, during which time he undertook an undergraduate research project in X-ray crystallography, fostering his strong interest in structural biology. He continued at Sheffield for his PhD studies, focusing on the development of new anti-malarial and toxoplasmosis compounds through X-ray crystallography. After a brief postdoctoral position in Sheffield studying the role of the GTPase EngA, he moved to Leeds in 2005 to learn electron microscopy (EM). During this time, he developed a keen interest in EM and its application for studying large membrane protein complexes, as well as new methodologies such as time-resolved cryoEM. Following the award of an MRC career development fellowship in 2010, he established his own research group with a strong interest in combining different techniques to study the structure and function of a wide range of protein targets. Dr Muench is currently an Associate Professor in Membrane Biology at the University of Leeds, where his group has worked on various systems and technologies, including the development of new small molecules, membrane protein scaffolds, biosensors, and time-resolved approaches. Major contributions to the field include the use of EM to drive inhibitor design for membrane proteins, development of time-resolved methodologies for cryoEM, and advancements in understanding sample preparation within single particle cryoEM.
Research interests
Dr Muench''s research focuses on structural biology, particularly the dynamics and conformational variability of large protein complexes. His work employs a combination of techniques, including X-ray crystallography and electron microscopy (EM), with an emphasis on time-resolved applications. He is involved in developing new approaches for sample preparation and time-resolved cryoEM studies, aiming to enhance the understanding of the structure/function relationship of medically important targets. Dr Muench''s research includes the development of time-resolved cryoEM methodologies, which allow for the trapping of dynamic protein states at various points in their movement. This involves collaboration with experts in engineering, mass spectrometry, and chemistry to create systems that can capture protein behaviours on the second, millisecond, and microsecond timescales. His group has also investigated the stability of samples for single particle cryoEM, revealing the time-dependent nature of sample stability and degradation. In addition, Dr Muench is focused on improving the study of membrane proteins, which are crucial for drug targeting but are less understood than soluble proteins. His research explores the use of styrene maleic acid (SMA) and related copolymers to extract and stabilise membrane proteins in a more native lipid environment. This work has led to significant advancements, including the first negative stain and sub-nanometre single particle cryoEM structure of an SMA-extracted membrane protein. Dr Muench''s interests also extend to structure-based drug design, where he aims to develop new small molecule inhibitors and understand disease-causing mutations across various diseases. His collaborative projects span multiple areas of biology, involving national and international partners, and include studies on TRPC channels, receptor tyrosine kinases, ABC transporters, and myosin, among others.
Membrane Biology
Structural Biology
Electron Microscopy
Membrane Proteins
Structure Based Drug Design
Time Resolved Electron Microscopy
Sample Preparation
X-Ray Crystallography
Protein Dynamics
CryoEM
Small Molecule Inhibitors
Protein Expression
Styrene Maleic Acid
Native Lipids
Drug Targeting
Biochemical Analysis
Protein Complexes
Biosensors
Method Development
Conformational Variability
Therapeutic Targets.
Career overview
Dr Antreas Kalli is an Associate Professor at the University of Leeds, specialising in molecular dynamics simulations, molecular modelling, and the study of membrane proteins and transporters. He holds a DPhil in Structural Biology from the University of Oxford, obtained in 2012, and a BSc in Physics from the University of Cyprus, awarded in 2008. Prior to his current role, Dr Kalli was a post-doctoral researcher in the Sansom group at the University of Oxford, where he employed computational methodologies to investigate the molecular functioning of membrane proteins. His research group focuses on using multi-scale molecular dynamics simulations and molecular modelling to explore the interactions and functions of proteins within cell membranes, particularly in relation to their lipid environments.
Research interests
Dr Kalli''s research focuses on the study of membrane proteins, which constitute approximately 25% of all genes and are significant drug targets. His group employs multi-scale molecular dynamics simulations and molecular modelling to elucidate the molecular and structural dynamics of these proteins within cell membranes and their interactions with lipid environments. A key aspect of the research involves simulating membrane proteins in complex model membranes that mimic their native environments, allowing for the investigation of how specific lipid molecules regulate protein function. The research spans several themes, including: - Ion Channels: Dr Kalli''s group uses molecular dynamics simulations to study mechanosensitive channels such as Piezo1, aiming to understand its activation mechanisms and regulation by small molecules and lipids. - Biologically Important Signalling Systems: The research includes examining the T-cell receptor''s activation and function at the molecular level, as well as how its activity is influenced by its lipid environment and cytosolic kinases. - Membrane Transport Proteins: The focus here is on proteins like Band 3 and members of the solute carrier (SLC) transporters, investigating their behaviour in cell membranes and their roles in transporting molecules across membranes. - Computational Methodologies: Dr Kalli''s group develops computational approaches to enhance the efficiency and speed of studying protein-lipid interactions. Overall, Dr Kalli''s work aims to provide deeper insights into the mechanisms of membrane proteins, which are crucial for understanding various biological processes and developing new therapeutic strategies.
Molecular Dynamics Simulations
Molecular Modelling
Membrane Proteins
Membrane Transporters
Cell Signalling
Mechanosensitive Channels
Ion Channels
T-Cell Receptor
Lipid Environment
Computational Approaches
Structural Biology
Drug Targets
Biologically Important Systems
Transport Proteins
Coarse-Grained Simulations
All-Atom Simulations
Protein Interactions
Cardiovascular Research.
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