Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34284-8
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Funding
- Vienna Science and Technology Fund (WWTF) [CS 15-033]
- Austrian Science Fund (FWF) [W1232]
- Stand-alone project [P34670-B20]
- Doctoral program Neuroscience [DOC33-B27]
- Theodor Korner Fonds
- Swiss National Science Foundation (SNSF) [P400PM_191032]
- Sinergia [198545]
- Lundbeck Foundation [R303-2018-3540]
- European Union [860954]
- Swiss National Science Foundation (SNF) [P400PM_191032] Funding Source: Swiss National Science Foundation (SNF)
- Marie Curie Actions (MSCA) [860954] Funding Source: Marie Curie Actions (MSCA)
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This study reports the structure of human organic cation transporter 3 (OCT3) and provides insight into its inhibition by two specific inhibitors, decynium-22 and corticosterone. Understanding OCT3 polymorphisms is important, and this research sheds light on their impact.
The current work reports the structure of the human organic cation transporter 3 (OCT3 / SLC22A3) and provides the structural basis of its inhibition by two specific inhibitors, decynium-22 and corticosterone. 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 angstrom 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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