IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-024-55361-0.html
   My bibliography  Save this article

Drug inhibition and substrate transport mechanisms of human VMAT2

Author

Listed:
  • Feiwen Wei

    (Fudan University)

  • Huihui Liu

    (The Chinese University of Hong Kong)

  • Wei Zhang

    (Fudan University)

  • Jufang Wang

    (Fudan University)

  • Yanqing Zhang

    (Fudan University)

Abstract

Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson’s disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders.

Suggested Citation

  • Feiwen Wei & Huihui Liu & Wei Zhang & Jufang Wang & Yanqing Zhang, 2025. "Drug inhibition and substrate transport mechanisms of human VMAT2," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55361-0
    DOI: 10.1038/s41467-024-55361-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-55361-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-55361-0?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. Shabareesh Pidathala & Shuyun Liao & Yaxin Dai & Xiao Li & Changkun Long & Chi-Lun Chang & Zhe Zhang & Chia-Hsueh Lee, 2023. "Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2," Nature, Nature, vol. 623(7989), pages 1086-1092, November.
    2. 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.
    3. Di Wu & Qihao Chen & Zhuoya Yu & Bo Huang & Jun Zhao & Yuhang Wang & Jiawei Su & Feng Zhou & Rui Yan & Na Li & Yan Zhao & Daohua Jiang, 2024. "Transport and inhibition mechanisms of human VMAT2," Nature, Nature, vol. 626(7998), pages 427-434, February.
    4. Ying Lyu & Chunting Fu & Haiyun Ma & Zhaoming Su & Ziyi Sun & Xiaoming Zhou, 2024. "Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    Full references (including those not matched with items on IDEAS)

    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. Pujun Xie & Yan Li & Gaëlle Lamon & Huihui Kuang & Da-Neng Wang & Nathaniel J. Traaseth, 2025. "A fiducial-assisted strategy compatible with resolving small MFS transporter structures in multiple conformations using cryo-EM," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    2. 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.
    3. Ying Lyu & Chunting Fu & Haiyun Ma & Zhaoming Su & Ziyi Sun & Xiaoming Zhou, 2024. "Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding," Nature Communications, Nature, vol. 15(1), pages 1-9, 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:16:y:2025:i:1:d:10.1038_s41467-024-55361-0. 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.