X-rays reveal protein structure
25 Nov 2011 by Evoluted New Media
For the first time, scientists have revealed the structure of a cholesterol-lowering-drug target, a finding which could lead to a more effective drug to tackle high levels of cholesterol, a condition that increases the risk of heart disease. Using intense X-ray beams from the Diamond Light Source in Oxfordshire and the European Synchrotron Radiation Facility (ESRF) in France, researchers from Imperial College London were able to determine the structure of a bacterial homologue of Apical Sodium dependent Bile Acid Transporter (ASBT).
“As some drugs are poorly absorbed in the intestine or need to be targeted to the liver, ASBT has received attention as a pro-drug carrier, capable of transporting various compounds coupled to bile acid,” said Dr Alexander Cameron from Imperial and the Membrane Protein Laboratory (MPL) at Diamond.
ABST is a membrane protein and an important drug target as it controls the level of cholesterol in the blood. In the liver, cholesterol makes bile acids which are used to absorb fat in the intestine –ASBT reabsorbs these bile acids, returning them to the liver. By blocking ASBT, bile acids levels returned to the liver are lowered, and the liver therefore converts more cholesterol into bile acids, lowering the level of cholesterol in the blood.
[caption id="attachment_24759" align="alignright" width="200" caption="Ribbon representation of ASBT bacterial homologue embedded in the membrane"]
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The synchrotrons were essential to screen ASBT crystals –which are notoriously hard to achieve – and collect the data used to obtain ASBT’s structure. Diamond also provided access to specialised equipment to dehydrate crystals, improving diffraction data and giving more accurate results.
This new-found knowledge – published in Nature – could have a wider impact on drug design.
“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,” said Professor So Iwata, David Blow Chair of Biophysics at Imperial and Director of the MPL.
Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT
