Zeng, Yi C. and Sobti, Meghna and Quinn, Ada and Smith, Nicola J. and Brown, Simon H. J. and Vandenberg, Jamie I. and Ryan, Renae M. and O’Mara, Megan L. and Stewart, Alastair G. (2023) Structural basis of promiscuous substrate transport by Organic Cation Transporter 1. Nature Communications, 14 (1). ISSN 2041-1723
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 01 May 2024 05:08 |
| Last Modified: | 01 May 2024 05:08 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1479 |
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