Beautiful biology from particle physics
BBSRC fellowship links life sciences to next-generation synchrotron
29 September 2009
Diamond Light Source (DLS) in Oxfordshire is one of the newest and most advanced synchrotron particle accelerators in the world. Completed in 2007 at an initial cost of £263M, Diamond represents the largest scientific facility to be built in the UK for 40 years.
Synchrotrons produce different kinds of light from across the electromagnetic spectrum. From x-rays to infra-red, this ‘synchrotron light’ is created by accelerating electrons to near the speed of light which is then used to delve into the structure of matter at the atomic level. It means that this 45,000 sq m cathedral to science is really one of the most powerful microscopes in the world (see Synchrotron science below)
Aerial view of the Diamond synchrotron
Particle accelerators are engineering marvels of the physical sciences but many discoveries may eventually come from biology because it’s what you put under the microscope that matters.
A guiding light
Championing the biological sciences is Professor So Iwata (see Profile and prize below), who, as part of the BBSRC’s Diamond Fellowship, will bring his research group from Imperial College to a new research complex currently being built next to Diamond.
Iwata will be using the powerful x-ray beams a quarter the width of human hair to decode complex proteins. He specialises in membrane proteins, the gateways that control what molecules pass in and out of cells and thus play a critical role in how cells react to nutrients, hormones and drugs.
So Iwata was awarded the Gregori Aminoff Prize 2010
“We are aiming to solve more membrane protein structures in this project,” says Iwata. “Membrane transporters are the gateways for the cells, responsible for taking up many different molecules.”
They are so important that various genome projects have shown that nearly one-third of proteins encoded by eukaryotic cells are membrane proteins.
But even though nearly half of commercially available drugs target them in some way, including Prozac, one of the most widely-prescribed drugs in the world, our knowledge of the precise structure and functioning of membrane proteins is embryonic. More than 30,000 protein structures have been mapped, but Iwata says that fewer than 200 of them are membrane proteins. “And much less than 10% of them are human membrane proteins, “ he adds.
Membrane proteins are notoriously difficult to crystallise
Image: So Iwata
Iwata is clearly the right man for the job, scooping the Gregori Aminoff Prize 2010 for his seminal crystallography studies. His group started work on membrane protein crystallography in 1992 and has solved almost a quarter of the membrane protein structures known by 2009.
Determining the structure of lactose permease in E. coli was a high point, earning them the cover of the prestigious Science journal in 2003 (ref 1).The enzyme helps pump the sugar lactose into cells and is a member of the major facilitator superfamily (MFS) of transport proteins which are found in almost every form of life.
In humans the MFS transporter controls increased glucose uptake in response to insulin stimulation. Understanding its structure, and therefore function, could lead to new treatments for diabetes, for example.
Other successes have included cytochrome c oxidase from two bacteria, cytochrome bc1 complex from bovine heart, and ubiquinol oxidase from E. coli. Based on these structures, knowledge of the causes of some genetic disorders has increased (ref 2).
In addition to his research group joining the new Research Complex at Harwell next to Diamond in 2010, for the past year Iwata has been leading the Membrane Protein Laboratory (MPL) based at Diamond itself. This separate investment from the Wellcome Trust offers crystallisation support to the UK community and will remain at Diamond.
An artist’s impression of the completed Research Complex
Image: Research Complex at Harwell
“I will do protein production in the Membrane Protein Crystallography (MPC) group in the research complex to feed proteins to MPL,” says Iwata. “The MPC group, Diamond and MPL will fully collaborate to solve membrane protein structures.”
Led by The Medical Research Council (MRC) on behalf of RCUK, the 6500 sq m site will provide facilities for cross-disciplinary research for physical and life scientists at Diamond, the ISIS neutron facility, and other shared facilities on the campus. Fields from genomics to nanotechnology; biological imaging and drug discovery hope to benefit from the development. “Crystallography is quite interdisciplinary,” says Iwata. “In our lab we combine life science, computer science and also engineering.”
The multi-disciplinary approach is needed because Iwata’s target, human transporter proteins, are among the most complex known. Moreover, all membrane proteins are difficult to produce in large amounts and are unstable.
But Iwata hopes a novel strategy that utilises antibodies will yield better results. “It's known that if you can make a stable complex of membrane protein and antibody that it facilitates membrane protein crystallisation," he says. "Recently we have developed a new method to raise antibodies. We have already obtained antibody complex crystals of several membrane proteins and have already corrected x-ray data from two of them at Diamond.”
- Diamond is currently the largest medium-energy synchrotron in the world. The main part of Diamond’s accelerator storage ring is 561m in circumference
- The electrons orbiting at Diamond could travel around the world 7.5 times in one second.
- Over 2 million working hours went into Diamond’s construction
- Diamond accelerates electrons to 3 Giga Electron Volts (GeV) – the same as moving them between the terminals of a giant 3,000 million volt battery
- Phase II funding of £120M for a further 15 beamlines was confirmed in October 2004; Diamond can host up to 40 beamlines
- There are more than 50 functioning synchrotrons in the world, of which Diamond is one of the newest third-generation devices
- Synchrotrons can follow reactions in real time, such as the crystallisation of cocoa butter which can improve chocolate and food manufacture
- Synchrotrons help scientists fight viruses. Drug discovery research against flu, and for the foot-and-mouth disease vaccine both benefited from synchrotron science
Iwata gained his PhD at the University of Tokyo in 1991. After postdoctoral research experience at Photon Factory, Japan, and at the Max-Planck-Institute for Biophysics, Germany, he became a lecturer at Uppsala University, Sweden, in 1996. He joined the UK’s Imperial College in 2000 and became Director of Centre for Structural Biology in January 2005 before taking up the inaugural BBSRC Diamond Fellow in 2009.
In recognition of his "seminal crystallographic studies of membrane proteins” Iwata was awarded the Gregori Aminoff Prize 2010. Awarded for the first time in 1979, the Aminoff Prize is intended to reward a documented, individual contribution in the field of crystallography, and takes place at the Royal Swedish Academy of Science’s annual meeting.
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- Science - Structure and Mechanism of the Lactose Permease of Escherichia coli (external link)
- Exercise Intolerance Due to Mutations in the Cytochrome b Gene of Mitochondrial DNA (external link)
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