Structural basis of bile acid lateral diffusion facilitated by the OSTα/β transporter

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Abstract
OSTα/β is the essential basolateral transporter responsible for returning reabsorbed bile acids to the portal circulation, yet its molecular mechanism remains unclear. Here, we report the cryo-electron microscopy structure of human OSTα/β at 2.7 Å resolution, revealing a GPCR-like 7-TM architecture distinct from all established SLC transporter folds. We further determined the taurocholate (TC)-bound structure at 3.2 Å, showing that the substrate laterally binds to a surface groove on OSTα, but not in the central cavity. The TC molecule is captured by a line of conserved polar residues along the groove, which were further proved by structure-guided mutagenesis combined with transport assays. Molecular dynamics simulations also suggest that it is energetically favored for TC moving along the surface groove. Together, structural analysis, functional assays, and simulations demonstrate that OSTα/β mediates bile acid transmembrane translocation via a facilitated lateral diffusion mechanism with subtle conformational change, which is distinct from known SLCs. These findings establish a mechanistic framework for OSTα/β function in enterohepatic bile acid circulation and provide a foundation for therapeutic modulation of bile acid homeostasis.

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