Bacteria display a variety of proteins on their surfaces which play important roles in the biology of the organism. Some are involved in uptake of nutrients, whereas others can act as antigens and play a part in the infection of human cells. The overall aim of my work is to understand the structures of these proteins, how they work and how they interact with the molecules of the human immune system. To do this we use a range of physical techniques, including X-ray crystallography and NMR, which provide us with an atomic level description of protein structure. This type of work then has a natural translation into applications in the area of vaccines. For example, I am currently working with colleagues on a new approach to the development of a vaccine against meningococcal meningitis.
I am currently Professor of Molecular Microbiology, working within the Microbiology Research Grouping in the Faculty. I obtained my first degree, and then PhD, from the University of Cambridge, before moving on to work in Prof Bill Shaw's group in Leicester. This gave me a background in the use of structural analysis in the study of protein function, as applied to the enzyme chloramphenicol acetyltransferase (CAT). I then obtained a Postdoctoral Research Fellowship from the Wellcome Trust, to work on the antibody-binding protein, Protein G, from Streptococcus, which is widely used in affinity resins for purifying antibodies. Working with Gordon Roberts and Lu-Yun Lian in the Biological NMR Centre in Leicester, we published the first description of the structure of this important protein. Working with Dale Wigley, we also determined the crystal structure of a Protein G domain bound to an Fab fragment, revealing the molecular basis for its recognition of antibody (Nature 359, 752-754). This started my interest in bacterial cell surface proteins- the structures they adopt, how they function and interact with the immune system. In 1993, I moved to UMIST as a lecturer, and have been at Manchester ever since. At this time, I started to work on the outer membrane proteins (OMPs) from Neisseria meningitidis, the causative agent of meningococcal meningitis. This work was initially funded through a Lister Fellowship, which I held between 1996 and 2001. Working with Mark Achtman's lab in Berlin, we were the first group to publish a crystal structure of an outer membrane protein from Neisseria, the OpcA protein (PNAS 99, 3417-3421). In parallel, I also investigated the interaction of the immune system with Neisserial OMPs, through collaborations with Martin Maiden (Oxford) and Ian Feavers (NIBSC). OMPs such as the PorA porin have been shown to provide protective immunity against meningococcal meningitis, and have been used as constituents of vaccines against the disease. This work has recently translated into Wellcome Trust Translation Award with Andrew Pollard (Oxford), Martin Maiden and Ian Feavers, aiming to develop a new approach to immunization against meningococcal disease. My lab has also focused on the biogenesis of type IV pili in Gram negative bacteria. Type IV pili play major roles in bacterial cell adhesion, DNA transformation and motility. They are assembled through the action of a complex group of proteins which span the inner and outer membranes, acting effectively as a macromolecular machine. In a collaboration with Tone Tonjum in Oslo and Bob Ford's group in Manchester, we have worked on the characterisation of the PilQ outer membrane secretin by electron microscopy (J Biol Chem 279, 39750-39756), revealing an unusual chamber-like structure which mediates the passage of type IV pili across the outer membrane. More recent work has concentrated on the determination of the structures of the component proteins within the assembly machine (eg J Mol Biol 364, 186-195) and earlier this year we published the first crystal structure of a complex between two type IV pilus assembly proteins (J Biol Chem 286, 24434-42).
I have always maintained a strong interest in commercial and industrial applications of my work. I was a co-founder, with Prof Bill Shaw and Drs Bill Primrose and Ann Lewendon, of a biotechnology/ pharmaceutical start-up company called PanTherix in 1997. More recently, I obtained a grant from BBSRC under the Bioprocessing Research Industry Club (BRIC) initiative, working with Jim Warwicker in my Faculty and Robin Curtis in Chemical Engineering. Our aim is to investigate better methods for understanding and predicting protein aggregation, which is a significant problem in the bioprocess industry.