IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59677-3.html
   My bibliography  Save this article

Structural basis of TMPRSS11D specificity and autocleavage activation

Author

Listed:
  • Bryan J. Fraser

    (Structural Genomics Consortium Toronto
    University of Toronto)

  • Ryan P. Wilson

    (Structural Genomics Consortium Toronto)

  • Sára Ferková

    (Université de Sherbrooke
    University of British Columbia)

  • Olzhas Ilyassov

    (Structural Genomics Consortium Toronto)

  • Jackie Lac

    (Structural Genomics Consortium Toronto)

  • Aiping Dong

    (Structural Genomics Consortium Toronto)

  • Yen-Yen Li

    (Structural Genomics Consortium Toronto)

  • Alma Seitova

    (Structural Genomics Consortium Toronto)

  • Yanjun Li

    (Structural Genomics Consortium Toronto)

  • Zahra Hejazi

    (Structural Genomics Consortium Toronto)

  • Tristan M. G. Kenney

    (University of Toronto
    Princess Margaret Cancer Centre)

  • Linda Z. Penn

    (University of Toronto
    Princess Margaret Cancer Centre)

  • Aled Edwards

    (Structural Genomics Consortium Toronto
    University of Toronto)

  • Richard Leduc

    (Université de Sherbrooke
    University of British Columbia)

  • Pierre-Luc Boudreault

    (Université de Sherbrooke
    University of British Columbia)

  • Gregg B. Morin

    (Canada’s Michael Smith Genome Sciences Centre
    British Columbia Cancer Research Institute
    University of British Columbia)

  • François Bénard

    (British Columbia Cancer Research Institute
    University of British Columbia)

  • Cheryl H. Arrowsmith

    (Structural Genomics Consortium Toronto
    University of Toronto
    Princess Margaret Cancer Centre)

Abstract

Transmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We show these proteases spontaneously and efficiently cleave their own zymogen activation motifs, activating their broader protease activity on cellular substrates. We determine TMPRSS11D co-crystal structures with a native and an engineered activation motif, revealing insights into its autocleavage activation and distinct substrate binding cleft features. Leveraging this structural data, we develop nanomolar potency peptidomimetic inhibitors of TMPRSS11D and TMPRSS2. We show that a broad serine protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. In this work, we develop mechanistic insights into human protease viral tropism and highlight both the strengths and limitations of existing human serine protease inhibitors, informing future drug discovery efforts targeting these proteases.

Suggested Citation

  • Bryan J. Fraser & Ryan P. Wilson & Sára Ferková & Olzhas Ilyassov & Jackie Lac & Aiping Dong & Yen-Yen Li & Alma Seitova & Yanjun Li & Zahra Hejazi & Tristan M. G. Kenney & Linda Z. Penn & Aled Edward, 2025. "Structural basis of TMPRSS11D specificity and autocleavage activation," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59677-3
    DOI: 10.1038/s41467-025-59677-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59677-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-59677-3?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. Gina L. Zoratti & Lauren M. Tanabe & Fausto A. Varela & Andrew S. Murray & Christopher Bergum & Éloïc Colombo & Julie E. Lang & Alfredo A. Molinolo & Richard Leduc & Eric Marsault & Julie Boerner & Ka, 2015. "Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    2. Haofeng Wang & Qi Yang & Xiaoce Liu & Zili Xu & Maolin Shao & Dongxu Li & Yinkai Duan & Jielin Tang & Xianqiang Yu & Yumin Zhang & Aihua Hao & Yajie Wang & Jie Chen & Chenghao Zhu & Luke Guddat & Hong, 2023. "Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. 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.
    4. Tirosh Shapira & I. Abrrey Monreal & Sébastien P. Dion & David W. Buchholz & Brian Imbiakha & Andrea D. Olmstead & Mason Jager & Antoine Désilets & Guang Gao & Mathias Martins & Thierry Vandal & Conno, 2022. "A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic," Nature, Nature, vol. 605(7909), pages 340-348, May.
    5. Xiaoli Yang & Zhanyu Ding & Lisi Peng & Qiuyue Song & Deyu Zhang & Fang Cui & Chuanchao Xia & Keliang Li & Hua Yin & Shiyu Li & Zhaoshen Li & Haojie Huang, 2022. "Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase," Nature Communications, Nature, vol. 13(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. 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.
    2. 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.
    3. 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.
    4. Pantelis Livanos & Choy Kriechbaum & Sophia Remers & Arvid Herrmann & Sabine Müller, 2025. "Kinesin-12 POK2 polarization is a prerequisite for a fully functional division site and aids cell plate positioning," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    5. 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.
    6. Surabhi Kokane & Ashutosh Gulati & Pascal F. Meier & Rei Matsuoka & Tanadet Pipatpolkai & Giuseppe Albano & Tin Manh Ho & Lucie Delemotte & Daniel Fuster & David Drew, 2025. "PIP2-mediated oligomerization of the endosomal sodium/proton exchanger NHE9," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    7. 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.
    8. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative Artificial Intelligence," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, pages 7-46, National Bureau of Economic Research, Inc.
    9. 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.
    10. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    11. Anthony C. Bishop & Glorisé Torres-Montalvo & Sravya Kotaru & Kyle Mimun & A. Joshua Wand, 2023. "Robust automated backbone triple resonance NMR assignments of proteins using Bayesian-based simulated annealing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Xin Yong & Guowen Jia & Qin Yang & Chunzhuang Zhou & Sitao Zhang & Huaqing Deng & Daniel D. Billadeau & Zhaoming Su & Da Jia, 2025. "Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    13. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    17. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    18. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Weizhu Huang & Nan Jin & Jia Guo & Cangsong Shen & Chanjuan Xu & Kun Xi & Léo Bonhomme & Robert B. Quast & Dan-Dan Shen & Jiao Qin & Yi-Ru Liu & Yuxuan Song & Yang Gao & Emmanuel Margeat & Philippe Ro, 2024. "Structural basis of orientated asymmetry in a mGlu heterodimer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Justin N. Vaughn & Sandra E. Branham & Brian Abernathy & Amanda M. Hulse-Kemp & Adam R. Rivers & Amnon Levi & William P. Wechter, 2022. "Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon," Nature Communications, Nature, vol. 13(1), pages 1-14, 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_s41467-025-59677-3. 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.