4N7W

Crystal Structure of the sodium bile acid symporter from Yersinia frederiksenii

4N7W の概要

• エントリーDOI: 10.2210/pdb4n7w/pdb
• 関連するPDBエントリー: 4N7X
• 分子名称: Transporter, sodium/bile acid symporter family, CITRIC ACID, [(Z)-octadec-9-enyl] (2R)-2,3-bis(oxidanyl)propanoate, ... (4 entities in total)
• 機能のキーワード: slc10, sodium symport, bile acid, membrane protein, structural genomics, psi-biology, new york consortium on membrane protein structure, nycomps, transport protein
• 由来する生物種: Yersinia frederiksenii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66543.51

構造登録者

Zhou, X.,Levin, E.J.,Zhou, M.,New York Consortium on Membrane Protein Structure (NYCOMPS) (登録日: 2013-10-16, 公開日: 2013-12-11, 最終更新日: 2024-02-28)

主引用文献

Zhou, X.,Levin, E.J.,Pan, Y.,McCoy, J.G.,Sharma, R.,Kloss, B.,Bruni, R.,Quick, M.,Zhou, M.
Structural basis of the alternating-access mechanism in a bile acid transporter.
Nature, 505:569-573, 2013

PubMed Abstract: Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na(+)-dependent bile acid transporters involved in enterohepatic recirculation, the Na(+)-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBT(NM)) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na(+) and a taurocholic acid. However, the structural changes that bring bile acid and Na(+) across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na(+) and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na(+).

PubMed: 24317697
DOI: 10.1038/nature12811

実験手法

X-RAY DIFFRACTION (1.951 Å)