IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34284-8.html
   My bibliography  Save this article

Structural basis of organic cation transporter-3 inhibition

Author

Listed:
  • Basavraj Khanppnavar

    (Laboratory of Biomolecular Research, Paul Scherrer Institute
    Institute of Molecular Biology and Biophysics, ETH Zurich)

  • Julian Maier

    (Medical University of Vienna)

  • Freja Herborg

    (University of Copenhagen)

  • Ralph Gradisch

    (Medical University of Vienna)

  • Erika Lazzarin

    (Medical University of Vienna)

  • Dino Luethi

    (Medical University of Vienna)

  • Jae-Won Yang

    (Medical University of Vienna)

  • Chao Qi

    (Laboratory of Biomolecular Research, Paul Scherrer Institute)

  • Marion Holy

    (Medical University of Vienna)

  • Kathrin Jäntsch

    (Medical University of Vienna)

  • Oliver Kudlacek

    (Medical University of Vienna)

  • Klaus Schicker

    (Medical University of Vienna)

  • Thomas Werge

    (Institute of Biological Psychiatry, Mental Health Services Copenhagen
    University of Copenhagen
    The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
    University of Copenhagen)

  • Ulrik Gether

    (University of Copenhagen)

  • Thomas Stockner

    (Medical University of Vienna)

  • Volodymyr M. Korkhov

    (Laboratory of Biomolecular Research, Paul Scherrer Institute
    Institute of Molecular Biology and Biophysics, ETH Zurich)

  • Harald H. Sitte

    (Medical University of Vienna)

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.

Suggested Citation

  • Basavraj Khanppnavar & Julian Maier & Freja Herborg & Ralph Gradisch & Erika Lazzarin & Dino Luethi & Jae-Won Yang & Chao Qi & Marion Holy & Kathrin Jäntsch & Oliver Kudlacek & Klaus Schicker & Thomas, 2022. "Structural basis of organic cation transporter-3 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34284-8
    DOI: 10.1038/s41467-022-34284-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34284-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-34284-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    2. Dong Deng & Pengcheng Sun & Chuangye Yan & Meng Ke & Xin Jiang & Lei Xiong & Wenlin Ren & Kunio Hirata & Masaki Yamamoto & Shilong Fan & Nieng Yan, 2015. "Molecular basis of ligand recognition and transport by glucose transporters," Nature, Nature, vol. 526(7573), pages 391-396, October.
    3. Tuo Zhang & Dexin Sui & Jian Hu, 2016. "Structural insights of ZIP4 extracellular domain critical for optimal zinc transport," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    4. Shangyu Dang & Linfeng Sun & Yongjian Huang & Feiran Lu & Yufeng Liu & Haipeng Gong & Jiawei Wang & Nieng Yan, 2010. "Structure of a fucose transporter in an outward-open conformation," Nature, Nature, vol. 467(7316), pages 734-738, October.
    5. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Yi C. Zeng & Meghna Sobti & Ada Quinn & Nicola J. Smith & Simon H. J. Brown & Jamie I. Vandenberg & Renae M. Ryan & Megan L. O’Mara & Alastair G. Stewart, 2023. "Structural basis of promiscuous substrate transport by Organic Cation Transporter 1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Kian Hong Kock & Patrick K. Kimes & Stephen S. Gisselbrecht & Sachi Inukai & Sabrina K. Phanor & James T. Anderson & Gayatri Ramakrishnan & Colin H. Lipper & Dongyuan Song & Jesse V. Kurland & Julia M, 2024. "DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Yafei Yuan & Fang Kong & Hanwen Xu & Angqi Zhu & Nieng Yan & Chuangye Yan, 2022. "Cryo-EM structure of human glucose transporter GLUT4," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Lukas Gerasimavicius & Benjamin J. Livesey & Joseph A. Marsh, 2022. "Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Johanna M. Kohlmayr & Gernot F. Grabner & Anna Nusser & Anna Höll & Verina Manojlović & Bettina Halwachs & Sarah Masser & Evelyne Jany-Luig & Hanna Engelke & Robert Zimmermann & Ulrich Stelzl, 2024. "Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Federica Luppino & Ivan A. Adzhubei & Christopher A. Cassa & Agnes Toth-Petroczy, 2023. "DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Mofan Feng & Xiaoxi Wei & Xi Zheng & Liangjie Liu & Lin Lin & Manying Xia & Guang He & Yi Shi & Qing Lu, 2024. "Decoding Missense Variants by Incorporating Phase Separation via Machine Learning," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Elizaveta Lyapina & Egor Marin & Anastasiia Gusach & Philipp Orekhov & Andrey Gerasimov & Aleksandra Luginina & Daniil Vakhrameev & Margarita Ergasheva & Margarita Kovaleva & Georgii Khusainov & Polin, 2022. "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Elisabeth Lambert & Ahmad Reza Mehdipour & Alexander Schmidt & Gerhard Hummer & Camilo Perez, 2022. "Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Dohyun Im & Mika Jormakka & Narinobu Juge & Jun-ichi Kishikawa & Takayuki Kato & Yukihiko Sugita & Takeshi Noda & Tomoko Uemura & Yuki Shiimura & Takaaki Miyaji & Hidetsugu Asada & So Iwata, 2024. "Neurotransmitter recognition by human vesicular monoamine transporter 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    10. Bian Li & Dan M. Roden & John A. Capra, 2022. "The 3D mutational constraint on amino acid sites in the human proteome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Matt C. Danzi & Maike F. Dohrn & Sarah Fazal & Danique Beijer & Adriana P. Rebelo & Vivian Cintra & Stephan Züchner, 2023. "Deep structured learning for variant prioritization in Mendelian diseases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    13. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Léon Faure & Bastien Mollet & Wolfram Liebermeister & Jean-Loup Faulon, 2023. "A neural-mechanistic hybrid approach improving the predictive power of genome-scale metabolic models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    15. Tian Zhu & Merry H. Ma, 2022. "Deriving the Optimal Strategy for the Two Dice Pig Game via Reinforcement Learning," Stats, MDPI, vol. 5(3), pages 1-14, August.
    16. Asmundur Oddsson & Patrick Sulem & Gardar Sveinbjornsson & Gudny A. Arnadottir & Valgerdur Steinthorsdottir & Gisli H. Halldorsson & Bjarni A. Atlason & Gudjon R. Oskarsson & Hannes Helgason & Henriet, 2023. "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    18. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    19. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    20. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34284-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.