Volume 33, No 12, Dec 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 12, December 2023: 940-951   |  Open Access

ORIGINAL ARTICLES

Cryo-EM structures of human organic anion transporting polypeptide OATP1B1

Ziyang Shan^1,† , Xuemei Yang^1,† , Huihui Liu^2,† , Yafei Yuan^3,† , Yuan Xiao^3,† , Jing Nan^1,† , Wei Zhang¹ , Wenqi Song³ , Jufang Wang¹ , Feiwen Wei¹ , Yanqing Zhang^1,*

¹Shanghai 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
²Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
³Beijing 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
^†These authors contributed equally: Ziyang Shan, Xuemei Yang, Huihui Liu, Yafei Yuan, Yuan Xiao, Jing Nan
Correspondence: Yanqing Zhang(zyq_lab@fudan.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00870-8

FULL TEXT | PDF

Browse 470