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Researchers in the Sir William Dunn School of Pathology, together with colleagues from across Oxford, have successfully obtained a structure of the surface layer from Gram-negative bacteria, bound to the cell membrane via long sugars called lipopolysaccharide or endotoxin, by applying novel electron tomography techniques.

This proof-of-concept study shows how structural biology is entering a new era, where it is possible to resolve atomic structures directly inside their native environment in cells.

DunnCellpaper2.jpgGram-negative bacteria are widespread, and include several human pathogens, causing antibiotic resistant infections, which are difficult to treat. Most bacteria are surrounded by a protective surface layer made of proteins, termed ‘S-layer’. Due to their copy numbers on prokaryotes (bacteria and archaea), S-layer proteins are the most abundant class of proteins on earth. Despite their abundance and importance, atomic resolution details of S-layers are not available, and S-layers remain an under-explored area of fundamental biology.

This recent study by Tanmay Bharat’s group, in collaboration with Carol Robinson’s group in Department of Chemistry and Phillip Stansfeld’s group in Department of Biochemistry, shows the power of integrated structural biology in resolving atomic structures from cells, and deducing complex biological mechanisms in situ. In addition to the surface layer structure reported, this study reports the native structure and arrangement of endotoxin or lipopolysaccharide, which is a ubiquitous molecule in Gram-negative bacteria, including several human pathogens, as it is found on cells.

This study will have important implications not only in the field of prokaryotic biology related to S-layers, but also in the future of structure-based drug design.