RT Journal Article
SR Electronic
T1 Structural basis of organic cation transporter-3 inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.14.499921
DO 10.1101/2022.07.14.499921
A1 Basavraj Khanppnavar
A1 Julian Maier
A1 Freja Herborg
A1 Ralph Gradisch
A1 Erika Lazzarin
A1 Dino Luethi
A1 Jae-Won Yang
A1 Chao Qi
A1 Marion Holy
A1 Kathrin Jäntsch
A1 Oliver Kudlacek
A1 Klaus Schicker
A1 Thomas Werge
A1 Ulrik Gether
A1 Thomas Stockner
A1 Volodymyr M. Korkhov
A1 Harald H. Sitte
YR 2022
UL http://biorxiv.org/content/early/2022/07/28/2022.07.14.499921.abstract
AB Organic cation transporters (OCTs) facilitate the translocation of catecholamines 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.Competing Interest StatementThe authors have declared no competing interest.