Structural insights into human polyspecific organic anion transporters OAT1 and OAT4
Summary: Organic anion transporters (OATs) play a critical role in the transport of organic anions. OAT1, located in the kidney, is essential for the transport of organic anion drugs and metabolites, while OAT4 facilitates absorption processes in the kidney and placenta. Here, we resolved the cryo-e...
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725007466 |
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| author | Wei Zhang Youfu Chu Ziyang Shan Huihui Liu Xuemei Yang Jing Nan Feiwen Wei Yanqing Zhang |
| author_facet | Wei Zhang Youfu Chu Ziyang Shan Huihui Liu Xuemei Yang Jing Nan Feiwen Wei Yanqing Zhang |
| author_sort | Wei Zhang |
| collection | DOAJ |
| description | Summary: Organic anion transporters (OATs) play a critical role in the transport of organic anions. OAT1, located in the kidney, is essential for the transport of organic anion drugs and metabolites, while OAT4 facilitates absorption processes in the kidney and placenta. Here, we resolved the cryo-electron microscopy structures of human OAT1 in its apo form and bound to probenecid, adefovir, cefazolin, and para-aminohippuric acid (PAH), as well as human OAT4 in its apo form and in complex with dehydroepiandrosterone sulfate (DHEAS). We observed a shared ligand-binding mode in OAT1 that appears to be common within the SLC22 family, characterized by two aromatic residues clamping the ligand and a pair of opposing charged residues that determine ligand orientation. DHEAS in OAT4 exhibits a different binding mode, illustrating the multispecific ligand-binding characteristics of OATs. Our findings provide a framework for drug design and management of drug-drug interactions involving OAT1. |
| format | Article |
| id | doaj-art-d6eec2e7e75c406d898c7b14d40e346c |
| institution | Matheson Library |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d6eec2e7e75c406d898c7b14d40e346c2025-07-11T04:31:14ZengElsevierCell Reports2211-12472025-07-01447115975Structural insights into human polyspecific organic anion transporters OAT1 and OAT4Wei Zhang0Youfu Chu1Ziyang Shan2Huihui Liu3Xuemei Yang4Jing Nan5Feiwen Wei6Yanqing Zhang7Shanghai 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 200032, ChinaShanghai 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 200032, ChinaShanghai 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 200032, ChinaArieh Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, ChinaShanghai 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 200032, ChinaShanghai 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 200032, ChinaShanghai 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 200032, ChinaShanghai 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 200032, China; Corresponding authorSummary: Organic anion transporters (OATs) play a critical role in the transport of organic anions. OAT1, located in the kidney, is essential for the transport of organic anion drugs and metabolites, while OAT4 facilitates absorption processes in the kidney and placenta. Here, we resolved the cryo-electron microscopy structures of human OAT1 in its apo form and bound to probenecid, adefovir, cefazolin, and para-aminohippuric acid (PAH), as well as human OAT4 in its apo form and in complex with dehydroepiandrosterone sulfate (DHEAS). We observed a shared ligand-binding mode in OAT1 that appears to be common within the SLC22 family, characterized by two aromatic residues clamping the ligand and a pair of opposing charged residues that determine ligand orientation. DHEAS in OAT4 exhibits a different binding mode, illustrating the multispecific ligand-binding characteristics of OATs. Our findings provide a framework for drug design and management of drug-drug interactions involving OAT1.http://www.sciencedirect.com/science/article/pii/S2211124725007466CP: Molecular biology |
| spellingShingle | Wei Zhang Youfu Chu Ziyang Shan Huihui Liu Xuemei Yang Jing Nan Feiwen Wei Yanqing Zhang Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 Cell Reports CP: Molecular biology |
| title | Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 |
| title_full | Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 |
| title_fullStr | Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 |
| title_full_unstemmed | Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 |
| title_short | Structural insights into human polyspecific organic anion transporters OAT1 and OAT4 |
| title_sort | structural insights into human polyspecific organic anion transporters oat1 and oat4 |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725007466 |
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