Cryo-EM structures of human organic anion transporting polypeptide OATP1B1  

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

机构地区：[1]Shanghai Fifth People’s Hospital,Fudan University,and Shanghai Key Laboratory of Medical Epigenetics,International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology),Institutes of Biomedical Sciences,Fudan University,Shanghai,China [2]Warshel Institute for Computational Biology,School of Medicine,The Chinese University of Hong Kong,Shenzhen,Guangdong,China [3]Beijing Frontier Research Center for Biological Structure,Beijing Advanced Innovation Center for Structural Biology,Tsinghua-Peking Joint Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing,China

出　　处：《Cell Research》2023年第12期940-951,共12页细胞研究（英文版）

基　　金：funded by the National Natural Science Foundation of China(32171196 to Y.Z.);Shanghai Rising-Star Program(21QA1401200 to Y.Z.);the National Key R&D Program of China(2021YFA1300101 to Y.Z.);Start-up funds from Fudan University and Shanghai Fifth People’s Hospital(2021IBSPI03 to Y.Z.);Shenzhen Natural Science Foundation Project(GXWD20201231105722002-20200831175432002 to H.L.).

摘　　要：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.

关 键 词：OATP1B1 DRUGS ENDOGENOUS 

分 类 号：R96[医药卫生—药理学]