中国科学院物理研究所姜道华团队研制了人胆汁酸转运体OSTα-OSTβ的结构与机制。该项研究成果发表在2026年1月28日出版的《自然》上。

在这里，研究团队展示了人OSTα/β与胆固醇和内源性底物复合物的低温电镜结构，阐明了OSTα/β功能的结构基础。OSTα/β以一种新的异二聚体的二聚体方式组装：两个OSTα单位形成同二聚体核心，两个OSTβ单位结合在外围。OSTα采用g蛋白偶联受体（GPCR）折叠，包含一个独特的富含半胱氨酸的环，具有7个棕榈酰化位点；它们与跨膜螺旋5和6合作，构成BA识别位点。OSTα中的一个正腔连接BA位点，并通过OSTα/β促进BAs的跨膜易位。总之，本研究揭示了OSTα/β的结构和转运机制，并为这一关键转运体在BA稳态中的结构-功能关系提供了见解。

据了解，胆汁酸（BAs）是一种重要的两亲性表面活性剂，在多种生理过程中起着多方面的调节作用，包括营养吸收和分布、脂质代谢和炎症。人体有机溶质转运蛋白αβ （OSTα–OSTβ，以下简称OSTα/β）是一种BA转运蛋白，在BAs的分泌和分布中起关键作用。OSTα/β的致病性突变与胆汁淤积有关。尽管OSTα/β在BA稳态中具有重要的功能，但该复合物的化学计量学和组装以及OSTα/β运输BA的分子机制尚不清楚。

附：英文原文

Title: Structure and mechanism of the human bile acid transporter OSTα–OSTβ

Author: Wang, Ke, Fan, Junping, Chen, Huiwen, Huang, Bo, Chi, Cheng, Yan, Rui, Wu, Di, Zhou, Feng, Zhang, Wenhua, Jiang, Juquan, Lei, Xiaoguang, Jiang, Daohua

Issue&Volume: 2026-01-28

Abstract: Bile acids (BAs) are crucial amphipathic surfactants that function as multifaceted regulators in various physiological processes, including nutrient absorption and distribution, lipid metabolism and inflammation1,2. The human organic solute transporter αβ (OSTα–OSTβ; hereafter referred to as OSTα/β) is a BA transporter that has a key role in the secretion and distribution of BAs3,4,5,6. Pathogenic mutations in OSTα/β have been associated with cholestasis7,8. Despite the functional importance of OSTα/β in BA homeostasis, the stoichiometry and assembly of the complex and the molecular mechanism that underlies BA transport by OSTα/β remain unknown. Here we present cryo-electron microscopy structures of human OSTα/β in complex with cholesterols and an endogenous substrate, elucidating the structural basis for the function of OSTα/β. OSTα/β is assembled in a novel dimer-of-heterodimers manner: two OSTα units form the homodimeric core, with two OSTβ units bound to the periphery. OSTα adopts the G-protein-coupled-receptor (GPCR) fold and contains a unique cysteine-rich loop with seven palmitoylation sites; these cooperate with transmembrane helices 5 and 6, constituting a BA recognition site. A positive cavity in OSTα connects the BA site and facilitates the transmembrane translocation of BAs through OSTα/β. Together, this study reveals the architecture and transport mechanism of OSTα/β and provides insights into the structure–function relationships of this crucial transporter in BA homeostasis.

DOI: 10.1038/s41586-025-09934-8

Source: https://www.nature.com/articles/s41586-025-09934-8