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Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT
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Hu, Nien-Jen, Iwata, So, Cameron, Alexander and Drew, David (2011) Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature, Vol. 478 (No. 7369). pp. 408-411. doi:10.1038/nature10450 ISSN 0028-0836.
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Official URL: http://dx.doi.org/10.1038/nature10450
Abstract
High cholesterol levels greatly increase the risk of cardiovascular disease. About 50 per cent of cholesterol is eliminated from the body by its conversion into bile acids. However, bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine by the apical sodium-dependent bile acid transporter (ASBT, also known as SLC10A2). It has been shown in animal models that plasma cholesterol levels are considerably lowered by specific inhibitors of ASBT1, 2, and ASBT is thus a target for hypercholesterolaemia drugs. Here we report the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBTNM) at 2.2 Å. ASBTNM contains two inverted structural repeats of five transmembrane helices. A core domain of six helices harbours two sodium ions, and the remaining four helices pack in a row to form a flat, ‘panel’-like domain. Overall, the architecture of the protein is remarkably similar to the sodium/proton antiporter NhaA3, despite having no detectable sequence homology. The ASBTNM structure was captured with the substrate taurocholate present, bound between the core and panel domains in a large, inward-facing, hydrophobic cavity. Residues near this cavity have been shown to affect the binding of specific inhibitors of human ASBT4. The position of the taurocholate molecule, together with the molecular architecture, suggests the rudiments of a possible transport mechanism.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Nature | ||||
Publisher: | Nature Publishing Group | ||||
ISSN: | 0028-0836 | ||||
Official Date: | 2011 | ||||
Dates: |
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Volume: | Vol. 478 | ||||
Number: | No. 7369 | ||||
Page Range: | pp. 408-411 | ||||
DOI: | 10.1038/nature10450 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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