Structural Biology in the RFI

Lead Research Organisation: University of Oxford
Department Name: Structural Biology

Abstract

The RFI is a UK government funded initiative that will bring together Academia and Industry to solve the most pressing problems in the life sciences (Industrial Biotechnology, Pharmaceutical, Agrichemical). It has a Hub at Harwell and currently ten University partners (Spokes). Its goal is to deliver innovative new physical science that will transform the life sciences. The RFI has five interlinked scientific themes; structural biology, next generation chemistry, imaging with sound and light, mass spectrometry and next generation electron microscopy.

Four broad areas of structural biology are identified where breakthroughs in the underlying methodology would be transformative. These are the extension to larger transient assemblies, the transformation of structure-guided drug discovery, reaching into the fourth (time) dimension and tackling unstructured proteins.
In order to deliver impact in these areas, the RFI will undertake research in new approaches to manipulating cells and macromolecules, sample preparation; novel sample delivery particularly to electron microscopes / tomographs; new hardware for imaging; correlating imaging data from different sources; in developing a new pipelines for fragment-based drug discovery; and in combining imaging modalities to reach into the time domain.
To realise these goals RFI requires a unique partnership between 10 Universities, the UK's central Facilities and most importantly UK Industry.

Planned Impact

Structural biology is an indispensable tool for understanding how life works in molecular terms and is an important tool in the development of new drugs to improve human health. Structural biology covers a wide range of experimental approaches from super resolution fluorescent microscopy, through electron and X-ray tomography, X-ray ptychography, electron microscopy, X-ray and electron diffraction and scattering, time-resolved X-ray diffraction, mass spectrometry, NMR and computational modelling. Underpinning all these techniques are advances in computational power and development of sophisticated software; it is essential that we proceed in a joined up-manner. Only by combining these techniques will we be able to analyse life from atoms to cells and to ultimately see that life in motion. Mass spectrometry, correlative imaging and chemical biology are also integral parts of any modern approach to structural biology. In particular structural biology, in partnership with chemistry and computational approaches is central to modern drug discovery.

The UK can fairly claim to have pioneered much of structural biology and today it remains recognised as a UK scientific strength. The 2017 Nobel Prize in Chemistry awarded to Richard Henderson and colleagues is the latest in a list of Nobel Prizes awarded to UK scientists in structural biology. This strength has created and sustained a vibrant industrial sector, ranging from large global pharmaceutical companies such as GSK and AZ, to rapidly growing drug companies that include Vernalis, Evotec and Astex to biotechnology firms, for example UCB-Celltech, Heptares and Immunocore that all rely on structural biology. This strength has attracted other multinational companies such as Vertex to base significant efforts in the UK. The Diamond Light Source's DISCO committee provides a focal point for this vibrant Industrial structural biology community. It is recognised that the cross-flow of ideas and people has been enormously beneficial to both Industry and to the wider Harwell Campus, particularly the Diamond Light Source. This proximity to Diamond is key to developing a vision for structural biology within the RFI. In setting out the technology drive for structural biology, we must first survey the key problems facing the field.

Publications

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