Structural basis of the alternating-access mechanism in a bile acid transporter

CORC > 昆明动物研究所 > 昆明动物研究所 > 动物模型与人类重大疾病机理重点实验室 > 离子通道药物研发中心

	Structural basis of the alternating-access mechanism in a bile acid transporter
	Zhou XM 1,2; Levin EJ 1; Pan YP 1; McCoy JG 1; Sharma R[2; Kloss B 3; Bruni R 3; Quick M[]4,5; Zhou M[]1,2,6
刊名	NATURE
	2014
卷号	505 期号:7484 页码:569-573
通讯作者	mq2102@columbia.edu ; mzhou@bcm.edu
合作状况	其它
英文摘要	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(1). 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(2). 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(3,4). 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(2,5-8). The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBT(NM)) in detergent was reported recently(9), 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 (ASBT(Yf)) 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+.
收录类别	SCI
语种	英语
WOS记录号	WOS:000329995000044
公开日期	2014-02-14
内容类型	期刊论文
源URL	[http://159.226.149.42:8088/handle/152453/7802]
专题	昆明动物研究所_离子通道药物研发中心
作者单位	1.Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. 2.Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA 3.USA. 2 Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. 3 4.Department of Psychiatry and Center for Molecular Recognition, Columbia University, New York, New York 10032, USA 5.New York State Psychiatric Institute, Division of Molecular Therapeutics, New York, New York 10032, USA. 6.Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
推荐引用方式 GB/T 7714	Zhou XM,Levin EJ,Pan YP,et al. Structural basis of the alternating-access mechanism in a bile acid transporter[J]. NATURE,2014,505(7484):569-573.
APA	Zhou XM.,Levin EJ.,Pan YP.,McCoy JG.,Sharma R[.,...&Zhou M[*].(2014).Structural basis of the alternating-access mechanism in a bile acid transporter.NATURE,505(7484),569-573.
MLA	Zhou XM,et al."Structural basis of the alternating-access mechanism in a bile acid transporter".NATURE 505.7484(2014):569-573.