Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 10 2023
11 10 2023
Historique:
received:
06
04
2023
accepted:
29
09
2023
medline:
1
11
2023
pubmed:
12
10
2023
entrez:
11
10
2023
Statut:
epublish
Résumé
Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.
Identifiants
pubmed: 37821493
doi: 10.1038/s41467-023-42086-9
pii: 10.1038/s41467-023-42086-9
pmc: PMC10567722
doi:
Substances chimiques
Organic Cation Transporter 1
0
Organic Cation Transport Proteins
0
Organic Cation Transporter 2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6374Subventions
Organisme : NIGMS NIH HHS
ID : U24 GM129547
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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