Bile acids are synthesized from cholesterol in hepatocytes and secreted via 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 re-secretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP or SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT or SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption,. However, a lack of 3-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 homolog from Neisseria meningitidis (ASBTNM) 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 better the structural changes associated with the coupled transport of Na+ and bile acids, we crystallized and solved two structures of a ASBT homolog from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives alternate accessibility to the highly conserved “crossover” region, where two discontinuous transmembrane helices cross each other. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na+.
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