Lowering cholesterol

Scientists from Imperial College London and Diamond Light Source have revealed the structure of a cholesterol-lowering-drug target. 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.¹

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.

Picture to the right shows a 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.

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.

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.”

Picture to the left shows a surface representation of ASBTnm looking from the inside face of the membrane showing bile acid bound in a deep cavity.

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."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.

The research was carried out across four sites: Imperial College London, the Research Complex at Harwell (RCaH), the Membrane Protein Laboratory at Diamond Light Source and the European Synchrotron Radiation Facility (ESRF). 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.

- ENDS -

‘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

References:

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.