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, Harald H Sitte

31 Citationer (Scopus)

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.

OriginalsprogEngelsk
Artikelnummer6714
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Sider (fra-til)6714
ISSN2041-1722
DOI
StatusUdgivet - dec. 2022

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