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

doi:10.1038/s41467-022-34284-8

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

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.

Original language	English
Article number	6714
Journal	Nature Communications
Volume	13
Issue number	1
Pages (from-to)	6714
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-022-34284-8
Publication status	Published - 7 Nov 2022

Keywords

Humans
Organic Cation Transport Proteins/genetics
Biological Transport
Corticosterone/pharmacology
Catecholamines
Cations/metabolism
Organic Cation Transporter 1/genetics
Organic Cation Transporter 2/metabolism

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Khanppnavar, B., Maier, J., Herborg, F., Gradisch, R., Lazzarin, E., Luethi, D., Yang, J-W., Qi, C., Holy, M., Jäntsch, K., Kudlacek, O., Schicker, K., Werge, T., Gether, U., Stockner, T., Korkhov, V. M., & Sitte, H. H. (2022). Structural basis of organic cation transporter-3 inhibition. Nature Communications, 13(1), 6714. [6714]. https://doi.org/10.1038/s41467-022-34284-8

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AU - Luethi, Dino

AU - Yang, Jae-Won

AU - Qi, Chao

AU - Holy, Marion

AU - Jäntsch, Kathrin

AU - Kudlacek, Oliver

AU - Schicker, Klaus

AU - Werge, Thomas

AU - Gether, Ulrik

AU - Stockner, Thomas

AU - Korkhov, Volodymyr M

AU - Sitte, Harald H

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N2 - 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.

AB - 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.

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Structural basis of organic cation transporter-3 inhibition

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