Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.

Autor: Zeng YC; Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia. y.zeng@victorchang.edu.au.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. y.zeng@victorchang.edu.au., Sobti M; Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia., Quinn A; Australian Institute of Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia., Smith NJ; School of Biomedical Sciences, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW, Australia., Brown SHJ; School of Chemistry and Molecular Bioscience, Molecular Horizons, and Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, University of Wollongong, Wollongong, NSW, Australia., Vandenberg JI; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.; Molecular Cardiology and Biophysics Division, The Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia., Ryan RM; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., O'Mara ML; Australian Institute of Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia., Stewart AG; Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia. a.stewart@victorchang.edu.au.; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. a.stewart@victorchang.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 11; Vol. 14 (1), pp. 6374. Date of Electronic Publication: 2023 Oct 11.
DOI: 10.1038/s41467-023-42086-9
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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