IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57956-7.html
   My bibliography  Save this article

The structural diversity of psychedelic drug actions revealed

Author

Listed:
  • Ryan H. Gumpper

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina)

  • Manish K. Jain

    (University of North Carolina at Chapel Hill School of Medicine)

  • Kuglae Kim

    (Yonsei University)

  • Renhong Sun

    (Icahn School of Medicine at Mount Sinai)

  • Ning Sun

    (Icahn School of Medicine at Mount Sinai)

  • Zhongli Xu

    (Icahn School of Medicine at Mount Sinai)

  • Jeffrey F. DiBerto

    (University of North Carolina at Chapel Hill School of Medicine
    LLC)

  • Brian E. Krumm

    (University of North Carolina at Chapel Hill School of Medicine)

  • Nicholas J. Kapolka

    (LLC)

  • H. Ümit Kaniskan

    (Icahn School of Medicine at Mount Sinai)

  • David E. Nichols

    (University of North Carolina)

  • Jian Jin

    (Icahn School of Medicine at Mount Sinai)

  • Jonathan F. Fay

    (University of Maryland Baltimore)

  • Bryan L. Roth

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina)

Abstract

There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT2A receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT2A activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.

Suggested Citation

  • Ryan H. Gumpper & Manish K. Jain & Kuglae Kim & Renhong Sun & Ning Sun & Zhongli Xu & Jeffrey F. DiBerto & Brian E. Krumm & Nicholas J. Kapolka & H. Ümit Kaniskan & David E. Nichols & Jian Jin & Jonat, 2025. "The structural diversity of psychedelic drug actions revealed," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57956-7
    DOI: 10.1038/s41467-025-57956-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57956-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57956-7?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. Carmen Klein Herenbrink & David A. Sykes & Prashant Donthamsetti & Meritxell Canals & Thomas Coudrat & Jeremy Shonberg & Peter J. Scammells & Ben Capuano & Patrick M. Sexton & Steven J. Charlton & Jon, 2016. "The role of kinetic context in apparent biased agonism at GPCRs," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    2. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Tao Che & Justin English & Brian E. Krumm & Kuglae Kim & Els Pardon & Reid H. J. Olsen & Sheng Wang & Shicheng Zhang & Jeffrey F. Diberto & Noah Sciaky & F. Ivy Carroll & Jan Steyaert & Daniel Wacker , 2020. "Nanobody-enabled monitoring of kappa opioid receptor states," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    4. Peiyu Xu & Sijie Huang & Huibing Zhang & Chunyou Mao & X. Edward Zhou & Xi Cheng & Icaro A. Simon & Dan-Dan Shen & Hsin-Yung Yen & Carol V. Robinson & Kasper Harpsøe & Bo Svensson & Jia Guo & Hualiang, 2021. "Structural insights into the lipid and ligand regulation of serotonin receptors," Nature, Nature, vol. 592(7854), pages 469-473, April.
    5. Can Cao & Hye Jin Kang & Isha Singh & He Chen & Chengwei Zhang & Wenlei Ye & Byron W. Hayes & Jing Liu & Ryan H. Gumpper & Brian J. Bender & Samuel T. Slocum & Brian E. Krumm & Katherine Lansu & John , 2021. "Structure, function and pharmacology of human itch GPCRs," Nature, Nature, vol. 600(7887), pages 170-175, December.
    6. Hideaki E. Kato & Yan Zhang & Hongli Hu & Carl-Mikael Suomivuori & Francois Marie Ngako Kadji & Junken Aoki & Kaavya Krishna Kumar & Rasmus Fonseca & Daniel Hilger & Weijiao Huang & Naomi R. Latorraca, 2019. "Conformational transitions of a neurotensin receptor 1–Gi1 complex," Nature, Nature, vol. 572(7767), pages 80-85, August.
    7. Anat Levit Kaplan & Danielle N. Confair & Kuglae Kim & Ximena Barros-Álvarez & Ramona M. Rodriguiz & Ying Yang & Oh Sang Kweon & Tao Che & John D. McCorvy & David N. Kamber & James P. Phelan & Luan Ca, 2022. "Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity," Nature, Nature, vol. 610(7932), pages 582-591, October.
    8. Antoine Koehl & Hongli Hu & Shoji Maeda & Yan Zhang & Qianhui Qu & Joseph M. Paggi & Naomi R. Latorraca & Daniel Hilger & Roger Dawson & Hugues Matile & Gebhard F. X. Schertler & Sebastien Granier & W, 2018. "Structure of the µ-opioid receptor–Gi protein complex," Nature, Nature, vol. 558(7711), pages 547-552, June.
    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. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    6. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Adam M. Zahm & William S. Owens & Samuel R. Himes & Braden S. Fallon & Kathleen E. Rondem & Alexa N. Gormick & Joshua S. Bloom & Sriram Kosuri & Henry Chan & Justin G. English, 2024. "A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    10. Chaehee Park & Jinuk Kim & Seung-Bum Ko & Yeol Kyo Choi & Hyeongseop Jeong & Hyeonuk Woo & Hyunook Kang & Injin Bang & Sang Ah Kim & Tae-Young Yoon & Chaok Seok & Wonpil Im & Hee-Jung Choi, 2022. "Structural basis of neuropeptide Y signaling through Y1 receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Naveen Thakur & Arka P. Ray & Liam Sharp & Beining Jin & Alexander Duong & Niloofar Gopal Pour & Samuel Obeng & Anuradha V. Wijesekara & Zhan-Guo Gao & Christopher R. McCurdy & Kenneth A. Jacobson & E, 2023. "Anionic phospholipids control mechanisms of GPCR-G protein recognition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    12. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    13. Yong-Seok Kim & Jun-Hee Yeon & Woori Ko & Byung-Chang Suh, 2023. "Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Yun-Tao Liu & Heng Zhang & Hui Wang & Chang-Lu Tao & Guo-Qiang Bi & Z. Hong Zhou, 2022. "Isotropic reconstruction for electron tomography with deep learning," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    15. Xinyu Zhang & Tianfang Zhao & Jiansheng Chen & Yuan Shen & Xueming Li, 2022. "EPicker is an exemplar-based continual learning approach for knowledge accumulation in cryoEM particle picking," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    16. Erumbi S. Rangarajan & Julian L. Bois & Scott B. Hansen & Tina Izard, 2024. "High-resolution snapshots of the talin auto-inhibitory states suggest roles in cell adhesion and signaling," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    17. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    19. Jia Liu & Cang Wu & Yuyang Liu & Qiangou Chen & Yuzhen Ding & Zhiqiao Lin & Lifeng Pan & Kang Xiao & Jianchao Li & Zhongmin Liu & Wei Liu, 2025. "Structural insights into the dual Ca2+-sensor-mediated activation of the PPEF phosphatase family," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    20. Jason Wallach & Andrew B. Cao & Maggie M. Calkins & Andrew J. Heim & Janelle K. Lanham & Emma M. Bonniwell & Joseph J. Hennessey & Hailey A. Bock & Emilie I. Anderson & Alexander M. Sherwood & Hamilto, 2023. "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential," Nature Communications, Nature, vol. 14(1), pages 1-19, 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_s41467-025-57956-7. 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.