Structural basis of organic cation transporter-3 inhibition

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  • Basavraj Khanppnavar
  • Julian Maier
  • Herborg, Freja
  • Ralph Gradisch
  • Erika Lazzarin
  • Dino Luethi
  • Jae Won Yang
  • Chao Qi
  • Marion Holy
  • Kathrin Jäntsch
  • Oliver Kudlacek
  • Klaus Schicker
  • Werge, Thomas
  • Gether, Ulrik
  • Thomas Stockner
  • Volodymyr M. Korkhov
  • Harald H. Sitte
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
OriginalsprogEngelsk
Artikelnummer6714
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Antal sider13
ISSN2041-1723
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
The research described in this publication was supported by the Vienna Science and Technology Fund (WWTF) [CS 15–033] (H.H.S.), Austrian Science Fund (FWF) doctoral program Molecular Drug Targets [W1232] (H.H.S.), stand-alone project P34670-B20 (H.H.S., T.S. and V.M.K.) and doctoral program Neuroscience [DOC33-B27] (H.H.S. and J.M.), Theodor Körner Fonds 2020 (J.M.), Swiss National Science Foundation (SNSF; grant No. P400PM_191032, D.L.; Sinergia grant No. 198545, V.M.K.), and the Lundbeck Foundation (R303-2018-3540, FH). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860954 (T.S.). We thank Michael Freissmuth and Richard Kammerer for critical comments on the manuscript. In addition, we thank the PSI EM Facility for their support: Emiliya Poghosyan and Elisabeth Müller-Gubler, as well as Miroslav Peterek and Bilal Qureshi (ScopeM, ETH Zurich) for their support in cryo-EM data collection. We also thank Pavel Afanasyev (CEMK, ETH Zurich) for his advice and help in cryo-EM data handling. In addition, we thank Spencer Bliven and Marc Caubet Serrabou (PSI) for their support in high performance computing. In addition, the results presented have, in part, been achieved using the Vienna Scientific Cluster.

Funding Information:
The research described in this publication was supported by the Vienna Science and Technology Fund (WWTF) [CS 15–033] (H.H.S.), Austrian Science Fund (FWF) doctoral program Molecular Drug Targets [W1232] (H.H.S.), stand-alone project P34670-B20 (H.H.S., T.S. and V.M.K.) and doctoral program Neuroscience [DOC33-B27] (H.H.S. and J.M.), Theodor Körner Fonds 2020 (J.M.), Swiss National Science Foundation (SNSF; grant No. P400PM_191032, D.L.; Sinergia grant No. 198545, V.M.K.), and the Lundbeck Foundation (R303-2018-3540, FH). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860954 (T.S.). We thank Michael Freissmuth and Richard Kammerer for critical comments on the manuscript. In addition, we thank the PSI EM Facility for their support: Emiliya Poghosyan and Elisabeth Müller-Gubler, as well as Miroslav Peterek and Bilal Qureshi (ScopeM, ETH Zurich) for their support in cryo-EM data collection. We also thank Pavel Afanasyev (CEMK, ETH Zurich) for his advice and help in cryo-EM data handling. In addition, we thank Spencer Bliven and Marc Caubet Serrabou (PSI) for their support in high performance computing. In addition, the results presented have, in part, been achieved using the Vienna Scientific Cluster.

Publisher Copyright:
© 2022, The Author(s).

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