Dr Stephen Muench

Profile

I studied for an undergraduate degree in Biochemistry and Microbiology at the University of Sheffield in 1997 during which time I undertook an undergraduate research project in X-ray crystallography, which fostered my strong interest in structural biology. Therefore, I continued in Sheffield for my PhD studies looking into the development of new anti-malarial and toxoplasmosis compounds through X-ray crystallography. After a brief postdoc in Sheffield studying the role of the GTPAse EngA I moved to Leeds in 2005 to learn electron microscopy (EM). During this time I was able to develop a keen interest in EM and its use for studying large membrane protein complexes and the development of new methodologies such as time-resolved cryoEM. After the award of an MRC career development fellowship in 2010 I was able to start my own group with a strong interest in combining different techniques to study the structure and function of a wide range of protein targets.

I am currently a Professor in membrane biology and structural biology at the University of Leeds. My group has worked on a range of different systems and technologies from developing new small molecules, membrane protein scaffolds, biosensors and time-resolved approaches. Major contributions to the field include: (i) The use of EM to drive inhibitor design for membrane proteins such as TRPC1 and the bc1 complex, (ii) development of time-resolved methodologies for cryoEM, (iii) better understanding of sample preparation within single particle cryoEM, (iv) work on SMA polymers and hybrid vesicles with block co-polymers to improve membrane protein lifetimes.

 

 

Group photo from 2024

 

Research interests

Overall Goal

One of the major challenges for structural biology is not just to resolve the structure of large protein complexes, but crucially also to appreciate the dynamics and conformational variability of such systems. These challenges are best met through a combination of techniques such as X-ray crystallography and Electron Microscopy (EM), in particular time-resolved applications. My research involves the development of new approaches to sample preparation and time-resolved cryoEM studies along with better ways to stabilise membrane proteins to allow us to better understand the structure/function relationship of a number of medically important targets.

Time resolved cryoEM & sample preparation

Proteins and protein complexes exist as dynamic systems that often rely on conformational changes to carry out their function. However, trapping these states when they do not exist in equilibrium is challenging and requires the development of new technologies. Simplistically we must find ways to trigger a reaction or response and then freeze the system at different points of its movement, much like how a camera will take a series of snapshots of a moving object to allow movies to be formed.  Working with collaborators in engineering, X-ray crystallography, Mass spectrometry and chemistry the group have developed several systems and approaches that allow us to trap states in the second, millisecond and micro second time-scale. These approaches have been used t study proteins such as myosin and viruses along with non-biological systems such as crystal growth. Through the groups work in time-resolved cryoEM we have started to better understand the processes that more generally apply to the preparation of samples for single particle cryoEM. Our work has shown for role of time on sample stability and how both chemical modifications and degradation may occur in a time-dependent manner. Further work is developing better tools to study protein behaviour in the thin film environment and provide better resource and understanding for one of the major bottlenecks in cryoEM.

Developing new ways to study membrane proteins

Despite the biological importance of membrane proteins and their relevance for drug targeting with over >60% of therapeutic targets being membrane proteins, our structural understanding of this class of proteins is much poorer than that of their soluble counterparts. There are a number of challenges associated with studying membrane proteins including difficulties in protein expression and the requirement to stabilise the protein outside of the membrane environment, usually with detergents. The group have been looking at the ability of styrene maleic acid (SMA) and related copolymers to extract membrane proteins from their lipid environment surrounded by more native lipid. This has been shown to improve stability of the membrane protein and the group published the first negative stain and sub nm single particle cryo-EM structure of an SMA extracted membrane protein. Future work is combining EM with mass spectrometry to study the role of native lipids in the stability of membrane proteins and the effect of overexpression on the native lipid environment.

Structure Based Drug Design
The development of the new methods and approaches underpins the groups work on the development of new small molecule inhibitors and/or a better understanding of disease causing mutations for a range of diseases. This includes TRPC channels and HPSD1 in cancer in collaboration with the Bon group, Receptor Tyrosine Kinases with the Breeze and Harrison groups, ABC transporters such as ATM1 and Comatose with the Callaghan and Baker group, QNOR with the Hasnain group, KCNT1 and its role in epilepsy with the Lippiat group and the muscle protein Myosin with the Scarff and White groups. These projects span a range of biology and include national, international and industrial collaborators providing a rich environment of expertise and experiences for the group.  

• Action in solution: Embedding new technology and new capability in Biomolecular Interactions in the University of Leeds
• State of the art electron detection for cyoEM at the Astbury Biostructure Laboratories
• Structures of full-length FGFR cancer fusions and disease mutants
• The chaperone cycle of fibroblast growth factor receptor kinases in molecular detail
• Understanding the rules of sample preparation for single particle cryoEM
• Understanding the structural basis of sodium-triggered activation of neuronal potassium channels
• Understanding the structural basis of sodium-triggered activation of neuronal potassium channels

Qualifications

• PhD 2004; BSc (Hons), Sheffield

Professional memberships

• Biochemical Society
• British Biophysics Society

Student education

My interests in structure based drug design is reflected in my role on the pharmacology team teaching in the areas of pharmacokinetics, computer driven drug design and structural biology.

Studentship information

Undergraduate project topics:

• Developing new inhibitors towards protozoan parasites
• Structural studies of membrane protiens

Postgraduate studentship areas:

• Structural and biochemical analysis of large protein complexes, in particular membrane bound complexes
• The development of the time-resolved cryo-EM methodologies
• Structure based inhibitor design of membrane proteins

PhD opportunities:

• BBSRC Doctoral training program: http://www.astbury.leeds.ac.uk/join/BBSRC/intro.php
• Cheney PhD Scheme
• MRC PhD program

See also:

• Faculty Graduate School
• FindaPhD Project details:
  • Project 43978

Research groups and institutes

• Integrative Membrane Biology