Structural basis of organic cation transporter-3 inhibition.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 11 2022
07 11 2022
Historique:
received:
17
05
2022
accepted:
19
10
2022
entrez:
7
11
2022
pubmed:
8
11
2022
medline:
10
11
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36344565
doi: 10.1038/s41467-022-34284-8
pii: 10.1038/s41467-022-34284-8
pmc: PMC9640557
doi:
Substances chimiques
Organic Cation Transport Proteins
0
Corticosterone
W980KJ009P
Catecholamines
0
Cations
0
Organic Cation Transporter 1
0
Organic Cation Transporter 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6714Informations de copyright
© 2022. The Author(s).
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