Structural basis of promiscuous substrate transport by Organic Cation Transporter 1

Yi C. Zeng (), Meghna Sobti, Ada Quinn, Nicola J. Smith, Simon H. J. Brown, Jamie I. Vandenberg, Renae M. Ryan, Megan L. O’Mara and Alastair G. Stewart ()
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Yi C. Zeng: The Victor Chang Cardiac Research Institute
Meghna Sobti: The Victor Chang Cardiac Research Institute
Ada Quinn: University of Queensland
Nicola J. Smith: Faculty of Medicine & Health, UNSW Sydney
Simon H. J. Brown: University of Wollongong
Jamie I. Vandenberg: Faculty of Medicine and Health, UNSW Sydney
Renae M. Ryan: Faculty of Medicine and Health, University of Sydney
Megan L. O’Mara: University of Queensland
Alastair G. Stewart: The Victor Chang Cardiac Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42086-9

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