Structural basis of promiscuous substrate transport by Organic Cation Transporter 1
Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psycholo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42086-9 |
| _version_ | 1797558153904128000 |
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| author | Yi C. Zeng Meghna Sobti Ada Quinn Nicola J. Smith Simon H. J. Brown Jamie I. Vandenberg Renae M. Ryan Megan L. O’Mara Alastair G. Stewart |
| author_facet | Yi C. Zeng Meghna Sobti Ada Quinn Nicola J. Smith Simon H. J. Brown Jamie I. Vandenberg Renae M. Ryan Megan L. O’Mara Alastair G. Stewart |
| author_sort | Yi C. Zeng |
| collection | DOAJ |
| description | Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1. |
| first_indexed | 2024-03-10T17:26:26Z |
| format | Article |
| id | doaj.art-7d16bee6f8884657b1aa4c5b3640243f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:26:26Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7d16bee6f8884657b1aa4c5b3640243f2023-11-20T10:10:01ZengNature PortfolioNature Communications2041-17232023-10-0114111410.1038/s41467-023-42086-9Structural basis of promiscuous substrate transport by Organic Cation Transporter 1Yi C. Zeng0Meghna Sobti1Ada Quinn2Nicola J. Smith3Simon H. J. Brown4Jamie I. Vandenberg5Renae M. Ryan6Megan L. O’Mara7Alastair G. Stewart8Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research InstituteMolecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research InstituteAustralian Institute of Bioengineering and Nanotechnology, University of QueenslandSchool of Biomedical Sciences, Faculty of Medicine & Health, UNSW SydneySchool of Chemistry and Molecular Bioscience, Molecular Horizons, and Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, University of WollongongSchool of Clinical Medicine, Faculty of Medicine and Health, UNSW SydneySchool of Medical Sciences, Faculty of Medicine and Health, University of SydneyAustralian Institute of Bioengineering and Nanotechnology, University of QueenslandMolecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research InstituteAbstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.https://doi.org/10.1038/s41467-023-42086-9 |
| spellingShingle | Yi C. Zeng Meghna Sobti Ada Quinn Nicola J. Smith Simon H. J. Brown Jamie I. Vandenberg Renae M. Ryan Megan L. O’Mara Alastair G. Stewart Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 Nature Communications |
| title | Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 |
| title_full | Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 |
| title_fullStr | Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 |
| title_full_unstemmed | Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 |
| title_short | Structural basis of promiscuous substrate transport by Organic Cation Transporter 1 |
| title_sort | structural basis of promiscuous substrate transport by organic cation transporter 1 |
| url | https://doi.org/10.1038/s41467-023-42086-9 |
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