X-rays help advance the battle against heart disease

Published in the journal Nature, this finding could lead to much more effective drugs to tackle high cholesterol levels, a condition that increases the risk of heart disease (ref 1).

Cartoon representation of the ASBTnm structure embedded in the membrane. The protein transports bile acids across the membrane. A bile acid has been trapped in a cavity on the inside face of the protein (shown in wine-red)

Cartoon representation of the ASBTnm structure embedded in the membrane. The protein transports bile acids across the membrane. A bile acid has been trapped in a cavity on the inside face of the protein (shown in wine-red). Energy to drive the transport is provided by sodium ions. Two sodium ions are bound to the structure and these are shown as pink spheres. Image: Diamond Light Source

The researchers from Imperial College London used intense X-rays, generated by the Diamond synchrotron and the European Synchrotron Radiation Facility (ESRF), to determine for the first time the structure of bacterial homologue of the Apical Sodium dependent Bile Acid Transporter (ASBT) protein, a target for hypercholesterolemia drugs since it can affect the level of cholesterol in the blood.

In the liver, cholesterol makes bile acids which are used in the intestine to absorb fat. These bile acids are then reabsorbed by ASBT to be transported to the liver and recycled. It is known that by blocking ASBT, bile acid levels returning to the liver are lowered, the liver therefore converts more cholesterol into bile acids, which lowers the level of cholesterol in the blood.

Professor So Iwata, David Blow Chair of Biophysics at Imperial College London, BBSRC Fellow and Director of the Membrane Protein Laboratory (MPL) at Diamond, said: “There are currently a number of existing ASBT inhibitors effective in animal models, which were developed without structural knowledge of the protein. Now that we know the shape and size of the drug-binding site within a bacterial model of the protein, this detailed structural information should enable the design of improved drugs which are much more targeted and will “fit” much better.”

This new knowledge could have a wider impact on drug design. Dr Alexander Cameron from Imperial College London and the Membrane Protein Laboratory at Diamond explains: “As some drugs are poorly absorbed in the intestine or need to be targeted to the liver, ASBT has also received attention as a pro-drug carrier, capable of transporting various compounds coupled to bile acid. This means that there could be scope to improve a number of drugs tackling different problems, for example, cytostatic compounds targeting liver tumours.”

Surface representation of ASBTnm looking from the inside face of the membrane showing bile acid bound in a deep cavity.

Surface representation of ASBTnm looking from the inside face of the membrane showing bile acid bound in a deep cavity.
Image: Diamond Light Source

ASBT is a membrane protein, one of over 7,000 within the human body, of which many are important drug targets. Over 50% of current commercially available drugs target membrane proteins but they are notoriously hard to crystallise – a step that is a pre-requisite in solving protein structures using a synchrotron. Dr David Drew, Royal Society Research Fellow in the Life Sciences Department at Imperial College London said: “Key to the success was to find a suitable detergent that yielded good protein crystals, this arduous task was facilitated greatly by a large-scale stability screen we carried out.” (ref 2)

The ESRF and Diamond Light Source were essential to screen their crystals and collect the data used to obtain the structure. At Diamond they were also able to access specialised equipment that dehydrates the crystals, improving the resolution of their diffraction data, thus leading to much more accurate results.

Beamline Scientist on macromolecular crystallography (MX) beamline I02, Dr Juan Sanchez-Weatherby, played a key role in the development of the crystal dehydration equipment. He says: “Since membrane proteins are so hard to crystallise, you have to make sure that you try everything possible to improve the quality of data you can extract from each crystal. I am very pleased that the technical effort we have put into this development has resulted in some great scientific results. We will continue to integrate this equipment to help our users with new, challenging projects.”

The research was carried out across three sites: Imperial College London, the Research Complex at Harwell (RCaH) and the Membrane Protein Laboratory at Diamond Light Source. The study was funded by the European Union and the Medical Research Council (MRC), and supported by the Biotechnology and Biological Sciences Research Council (BBSRC), the ERATO IWATA Human Receptor Crystallography Project and the Wellcome Trust.


Notes to editors

Paper: ‘Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT’
Nien-Jen Hu, So Iwata, Alexander D. Cameron, David Drew
DOI: 10.1038/nature10450


  1. In 2009, over 180,000 people died from cardiovascular disease (CVD) in the UK – one in three of all deaths. Source: British Heart Foundation
  2. Benchmarking membrane protein detergent stability for improving throughput of high-resolution X-ray structures.Structure. 2011 Jan 12;19(1):17-25

About Diamond Light Source

Diamond Light Source produces the extremely intense X-ray beams required for looking at the molecular interactions involved in a variety of biological processes. Advances in structural biology have accelerated greatly as a result of access to the synchrotron facilities that have been developed around the world in the past 25 years. Researchers in the UK are at the forefront of this work and Diamond Light Source provides cutting edge facilities for protein structure determination.

Diamond currently has five experimental stations dedicated to structural biology as well as the on-site Membrane Protein Laboratory, recently developed in partnership with Imperial College London and funded by the Wellcome Trust. Since Diamond opened in 2007, over 500 protein structures have been solved there including enzymes associated with hypertension, tuberculosis and HIV.

  • Diamond Light Source is funded by the UK Government via the Science and Technology Facilities Council (STFC) and by the Wellcome Trust.
  • For more information about Diamond visit www.diamond.ac.uk
  • Diamond generates extremely intense pin-point beams of synchrotron light of exceptional quality ranging from X-rays, ultra-violet and infrared. For example Diamond’s X-rays are around 100 billion times brighter than a standard hospital X-ray machine.
  • Many of our everyday commodities that we take for granted, from food manufacturing to cosmetics, from revolutionary drugs to surgical tools, from computers to mobile phones, have all been developed or improved using synchrotron light.

About Imperial College London

Consistently rated amongst the world’s best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment – underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial’s contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of a all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.

In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK’s first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

Website: www.imperial.ac.uk
Twitter: www.twitter.com/imperialspark
Podcast: www.imperial.ac.uk/media/podcasts

About the Medical Research Council

For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

About the Research Complex at Harwell

The Research Complex at Harwell (RCaH) is a new, multidisciplinary laboratory that provides facilities for researchers to undertake new and cutting edge scientific research in both life and physical sciences and the interface between them. It is located on the Rutherford Appleton Laboratory (RAL) site on the Harwell Science and Innovation Campus, adjacent to Diamond, the new third generation Synchrotron Radiation (SR) source. The MRC is leading the project on behalf of RCUK, in partnership with BBSRC, EPSRC, NERC, STFC and Diamond.


BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, and with an annual budget of around £445M, we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: www.bbsrc.ac.uk.
For more information about BBSRC strategically funded institutes see: www.bbsrc.ac.uk/institutes.

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