BBSRC Portfolio Analyser
Award details
X-ray Diffraction Equipment for Macromolecular Crystallography at York
Reference
BB/T017805/1
Principal Investigator / Supervisor
Professor Gideon Davies
Co-Investigators /
Co-Supervisors
Professor Fred Anston
,
Professor Andrzej Brzozowski
,
Professor Kevin Cowtan
,
Dr Martin Fascione
,
Professor Gideon Grogan
,
Professor Jeremy Mottram
,
Dr Michael Plevin
,
Professor Gavin Thomas
,
Professor Anthony Wilkinson
,
Dr Lianne Willems
,
Professor Keith Wilson
Institution
University of York
Department
Chemistry
Funding type
Research
Value (£)
750,000
Status
Completed
Type
Research Grant
Start date
18/09/2020
End date
17/09/2022
Duration
24 months
Abstract
YSBL is a centre in Structural Biology with a core of 80 or so scientists distributed across a dozen or so research groups. Through collaborations, its research reaches across the York campus and extends to national and international laboratories as well as into industry. Its research has had three principal foci (i) the determination of protein crystal structures which have shaped our understanding of aspects of biological function, (ii) the application of structure in developing new products and processes and (iii) the development of methods of protein structure solution, refinement and analysis contributing to software, often distributed through CCP4, that is used throughout the world. The nature and the volume of the research we carry out requires that we maintain an X-ray diffraction system in the laboratory. Since 2010, an average of 3000 crystals per year have been tested on our in-house system. Of these, approximately 1000 were sent to the DIAMOND Light Source for high-resolution data collection making efficient use of the precious time allotted to us as part of a Beam Allocation Group (BAG). The productivity of the laboratory can be judged by the 674 coordinate sets deposited in the Protein Data Bank which have underpinned 310 papers published since 2010. Here we are requesting funds to replace and augment our X-ray diffraction apparatus which has served us well since 2007. We plan to house the new system consisting of an X-ray generator, a pixel array detector and an automated sample changer in a new building, currently under construction. This building will additionally accommodate a new cryoelectron microscope and an existing 700 MHz NMR spectrometer as part of a Structural Molecular Biology suite. The new equipment will support established research in Mechanistic Biology, Industrial Enzymes, Industrial Biotechnology and Drug Discovery as well as recently launched initiatives in Glycobiology and Chemical Biology.
Summary
Understanding molecular structure, that is the 3D shape of a molecule, is often the key to understanding how that molecule performs its function. This is particularly true for large biological molecules that orchestrate the biochemical processes that maintain living cells. An important method of determining the structure of proteins is first to grow crystals of these proteins and then to record their scattering of X-rays by what is termed X-ray diffraction. By collecting a series of X-ray images at different crystal orientations, we accumulate three-dimensional data sets consisting of 10,000 - 500,000 'observations'. Using computational methods we can then use these data to 'solve' (define the positions of atoms) the structure of the protein as it exists in the crystal. With its broad interest in the biological mechanisms of protein action and the exploitation of proteins for biotechnological and biomedical applications, the Structural Biology Laboratory generates 1000s of protein crystals a year. Here we are requesting funds to renew our suite of X-ray diffraction equipment including an X-ray generator, a detector for measuring X-ray diffraction by crystals, and a robot arm that can automatically and serially place crystals into the X-ray beam. Using this apparatus, we can test approximately 3000 crystals each year. We reject crystals that are of insufficient quality for structure determination and we prioritise the best crystals (~1000) for data collection. These crystals are sent to a synchrotron, the DIAMOND Light Source (DLS), a national facility where super-intense X-ray beams are generated. At DLS we can obtain high resolution diffraction data rapidly and accurately. Beam time at DLS is a valuable and limited resource and demand for beam time exceeds beam availability. Our laboratory has one shift every month on average. For this reason, the pre-screening of crystals in our own laboratory is essential for the efficient use of the DLS resource, so that the beam time is used to collect useful data rather than crystal testing. The productivity of the laboratory is evidenced by the submission of ~700 crystal structures into a publicly accessible database, called the Protein Data Bank, and the publication in peer-reviewed journals of 310 papers describing these structures. The structures we have determined are underpinning the development of improved washing powders, the science of biomass conversion for biofuels and the development of new medicines.
Impact Summary
The research of the Laboratory conforms to the paradigm that Impact derives from Excellence. Historically, the expertise of the laboratory in protein crystal structure determination led to very high productivity in this area and publications with high academic impact. This in turn drew interest from industry, leading to industrial collaborations and developing an industry facing culture. Evidence of this impact comes from the REF 2014 return with the work of the Laboratory contributing to four 'Impact Case Studies' these being on Designer Insulins, Industrial Enzymes in various applications including washing powders, Antifreeze Proteins in Ice Cream Technology and Crystallographic Software. All of these case studies built on accomplishments in protein crystallography at the heart of which are the diffraction data that we collect. The Laboratory has a continuing record of strength and depth in publications. In the period 2015-2019, the laboratory contributed to 232 new publications with its cumulative work attracting 38,659 citations in the same time interval. This speaks to the broad academic impact our research is having. We expect this trend to continue. Similarly, the applicants have new and contenting industrial collaborations such as those with Novozymes (Davies and Wilson), Unilever (Thomas with Wilkinson), GSK (Mottram with Wilkinson). The exact Impact that will be derived and the Pathways we will follow to Impact, will be project dependent and reflected in the individual project/programme grants whose future science this equipment will enable. Nevertheless exemplars include: Industrial. We work on diverse areas of biomass conversion, biocatalysis and greener technologies. The degradation of plant-derived biomass is one of the key objectives of BBSRC policy, UK government policy and of many UK and European Biotechnology companies. The same is true for our biocatalysts work. Therefore, the spectrum of "stakeholders" in the Structural Biology results generated through the work enabled by the new equipment enables is very broad indeed. There are obvious "day-to-day" benefits to the wider public as well as the potentially massive benefits of reducing fossil fuel usage, allowing greener industries, and fuel security as part of a balanced UK energy portfolio. Health The Bioscience for Health portfolio provides considerable wider impact, from basic understanding of health and disease, through clinical diagnostics, chaperones, enabling technologies and enzyme inhibitors as potential drugs. There is clearly a diverse wider audience for such work. Regional Scientists beyond YSBL. Importantly, we will make our X-ray equipment available to colleagues in Leeds and Sheffield (see letters of support) to use on a 'when needed' basis.
Committee
Not funded via Committee
Research Topics
Structural Biology
Research Priority
X – Research Priority information not available
Research Initiative
Advanced Life Sciences Research Technology Initiative (ALERT) [2013-2014]
Funding Scheme
X – not Funded via a specific Funding Scheme
I accept the
terms and conditions of use
(opens in new window)
export PDF file
back to list
new search