复旦大学生物医学研究院张琰青团队揭示人类有机阴离子转运多肽OATP1B1的冷冻电镜结构。这一研究成果于2023年9月6日在线发表在国际学术期刊《细胞研究》上。

研究人员表示，溶质载体有机阴离子转运多肽（OATP）家族的成员可转运多种两性有机阴离子，包括内源性代谢产物和临床药物，如胆汁盐、类固醇、甲状腺激素、他汀类药物、抗生素、抗病毒药物和抗癌药物。OATP1B1在将这类物质转运到肝脏进行肝清除方面起着至关重要的作用。FDA和EMA建议对涉及OATP1B1的药物间相互作用（DDI）进行体外测试。

研究人员测定了人OATP1B1在外向和内向开放状态下与代表性内源性代谢物（胆红素和 3-硫酸雌酮）、一种临床药物（simeprevir）和一种荧光指示剂（2′,7′-二氯荧光素）结合的冷冻电镜结构。这些结构揭示了主要和次要底物结合口袋以及运输过程中的构象变化。结合诱变研究和分子动力学模拟，这项工作全面阐明了OATP1B1的转运机制，并为OATP1B1的DDI预测提供了结构基础，这将极大地促进人们对OATP的了解。

附：英文原文

Title: Cryo-EM structures of human organic anion transporting polypeptide OATP1B1

Author: Shan, Ziyang, Yang, Xuemei, Liu, Huihui, Yuan, Yafei, Xiao, Yuan, Nan, Jing, Zhang, Wei, Song, Wenqi, Wang, Jufang, Wei, Feiwen, Zhang, Yanqing

Issue&Volume: 2023-09-06

Abstract: Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug–drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2′,7′-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.

DOI: 10.1038/s41422-023-00870-8

Source: https://www.nature.com/articles/s41422-023-00870-8