Structural basis of organic cation transporter-3 inhibition
Open accessPublished version of a preprint
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.
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- Authors
- 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.
- Affiliations
- Paul Scherrer Institute (CH)
- Medical University of Vienna (AT)
- University of Copenhagen (DK)
- Corresponding author
- Stockner, Thomas
- Korkhov, Volodymyr M.
- Sitte, Harald H.
- ORCID
- Venue
- Nature Communications
- Published
- 2022-11-07
- Volume
- 13
- Issue
- 1
- Pages
- 6714-6714
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9640557
- OpenAlex
- W4308768440
- Cited by
- 77
- References
- 4
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 18 · 2023: 21 · 2022: 3
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection
- Funders
- National Science Foundation
- European Commission (860954, HORIZON2020)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (191032, 198545)
- Vienna Science and Technology Fund (CS15-033)
- Austrian Science Fund (DOC 33, P 34670, W1232, DOC33‐B27)
- Eidgenössische Technische Hochschule Zürich
- Lundbeckfonden (R276- 2018-792, R155-2014-1724, R302-2018-2155, R204-2015-4129, R171-2014-1194, R341-2020-222, R248‐2017‐2003, R359-2020-2301, R24-2008-3243, R364-2021-85, R303-2018-3540)
- H. Lundbeck A/S
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- OCT3, major facilitator superfamily, transporter inhibition, cryo-EM structure, corticosterone, decynium-22, binding pocket, monoamine transport, genetic variants, polymorphism, drug transport
- MeSH terms
- Organic Cation Transporter 2, Biological Transport, Catecholamines, Cations, Corticosterone, Humans, Organic Cation Transport Proteins, Organic Cation Transporter 1
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