Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this techn ....Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this technology, which will assess target-drug interactions by in-cell electron paramagnetic resonance (EPR) spectroscopy. The techniques offer scope for accelerated drug development in the pharmaceutical industries.Read moreRead less
New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine resi ....New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine residues site-specifically introduced into proteins. These tags will also enable accurate distance measurements by electron paramagnetic resonance (EPR) spectroscopy in large, biologically important protein systems hitherto not amenable to detailed structural studies and in proteins undergoing conformational changes. Read moreRead less
The role of low-energy excited states in solar-energy capture. This project aims to determine the nature and role of the lowest-energy excited states in most natural photosynthetic reaction centres and light-harvesting complexes. The lowest-energy states of bacterial reaction centres are critical to function and are used as a paradigm in artificial organic solar-energy capture, but for most photosystems their nature remains unknown. The project aims to answer the critical question of why they do ....The role of low-energy excited states in solar-energy capture. This project aims to determine the nature and role of the lowest-energy excited states in most natural photosynthetic reaction centres and light-harvesting complexes. The lowest-energy states of bacterial reaction centres are critical to function and are used as a paradigm in artificial organic solar-energy capture, but for most photosystems their nature remains unknown. The project aims to answer the critical question of why they do not actually prevent function. It is expected that both the outcomes obtained and techniques developed will be directly relevant to solar-energy device design. The project will apply five existing, complimentary and purposely built spectrometers as well as quantum electronic and nuclear simulation techniques to identify and characterise three key systems.Read moreRead less
Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolu ....Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolution crystal structures are being used to identify function. Intriguingly, preliminary data indicates that the mutations do not affect the native antibody structure, but rather influence dynamic states. The project plans to use a combination of mutagenesis, molecular dynamics simulation and deuterium exchange to study antibody dynamics.Read moreRead less
Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonst ....Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonstrates that such a primordial receptor can in principle be reconstructed and characterised. The project proposes to expand this work, which will provide intriguing insights into antigen receptor evolution. The reconstruction of basic recognition modules will also be highly beneficial for biosensor applications. Read moreRead less
Artificially building the bacterial flagellar motor. This project will allow us to learn how nature’s most sophisticated rotary motor works and how to build these artificially, establishing a new field of research into man-made biological machines. This has potential applications for the emerging field of nanotechnology to make nanometre-scale devices that are powered by efficient biological machines.
A portable RNA-editing machine. Many plants maintain an elaborate RNA-editing machine that allows them to correct accumulated errors in their organellar genomes by specifically editing the RNA transcripts of the affected genes. A portable and adaptable version of this molecular machine would have significant biotechnological value, providing the ability to correct genetic errors, and to intervene in gene regulation without permanently altering a genome. The project aims to combine molecular and ....A portable RNA-editing machine. Many plants maintain an elaborate RNA-editing machine that allows them to correct accumulated errors in their organellar genomes by specifically editing the RNA transcripts of the affected genes. A portable and adaptable version of this molecular machine would have significant biotechnological value, providing the ability to correct genetic errors, and to intervene in gene regulation without permanently altering a genome. The project aims to combine molecular and structural biology approaches to fully characterise the components of the machine, thus allowing us to reconstitute it in cell-free systems and ultimately in other organisms.Read moreRead less
Phage display derived antibody fragments for membrane protein research. Membrane proteins are key components of all living organisms and represent more than 50 per cent of all drug targets. This project will redefine the way membrane proteins are studied and will be highly beneficial to basic research, human disease and the biotechnology industry.
Protein structure controls light harvesting in photosynthetic light algae. The strange phenomena of quantum mechanics were not expected to play a direct role in life, however, it appears that quantum effects may be important in the efficient capture of sunlight for photosynthesis. The conditions for the emergence of quantum phenomena appear to be set by the structures of proteins. The aim of this project is to relate protein structure to the emergence of quantum effects in the light harvesting p ....Protein structure controls light harvesting in photosynthetic light algae. The strange phenomena of quantum mechanics were not expected to play a direct role in life, however, it appears that quantum effects may be important in the efficient capture of sunlight for photosynthesis. The conditions for the emergence of quantum phenomena appear to be set by the structures of proteins. The aim of this project is to relate protein structure to the emergence of quantum effects in the light harvesting proteins of marine algae. Understanding the link between structure and quantum effects could improve our knowledge of how nature achieves its remarkable efficiency in utilising the energy from the sun. This is likely to foster new technologies that improve the efficiency of solar energy systems.Read moreRead less
All in the family: understanding a new class of bacterial toxins. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. The outcomes could reveal novel mechanisms general to these proteins and ....All in the family: understanding a new class of bacterial toxins. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. The outcomes could reveal novel mechanisms general to these proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this knowledge may guide the design of artificial protein pores that are selective for specific molecules with applications such as measuring metal ions, sugars, pesticides or pollutants. Read moreRead less