Structural basis of organic cation transporter-3 inhibition

Basavraj Khanppnavar, Julian Maier, Freja Herborg, Ralph Gradisch, Erika Lazzarin, Dino Luethi, Jae-Won Yang, Chao Qi, Marion Holy, Kathrin Jäntsch, Oliver Kudlacek, Klaus Schicker, Thomas Werge, Ulrik Gether, Thomas Stockner (), Volodymyr M. Korkhov () and Harald H. Sitte ()
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Basavraj Khanppnavar: Laboratory of Biomolecular Research, Paul Scherrer Institute
Julian Maier: Medical University of Vienna
Freja Herborg: University of Copenhagen
Ralph Gradisch: Medical University of Vienna
Erika Lazzarin: Medical University of Vienna
Dino Luethi: Medical University of Vienna
Jae-Won Yang: Medical University of Vienna
Chao Qi: Laboratory of Biomolecular Research, Paul Scherrer Institute
Marion Holy: Medical University of Vienna
Kathrin Jäntsch: Medical University of Vienna
Oliver Kudlacek: Medical University of Vienna
Klaus Schicker: Medical University of Vienna
Thomas Werge: Institute of Biological Psychiatry, Mental Health Services Copenhagen
Ulrik Gether: University of Copenhagen
Thomas Stockner: Medical University of Vienna
Volodymyr M. Korkhov: Laboratory of Biomolecular Research, Paul Scherrer Institute
Harald H. Sitte: Medical University of Vienna

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.

Date: 2022
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DOI: 10.1038/s41467-022-34284-8

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