IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58902-3.html
   My bibliography  Save this article

Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis

Author

Listed:
  • Adrián González-López

    (Uppsala University, BMC
    Uppsala University)

  • Xueliang Ge

    (Uppsala University, BMC)

  • Daniel S. D. Larsson

    (Uppsala University, BMC)

  • Carina Sihlbom Wallem

    (Scilifelab and University of Gothenburg)

  • Suparna Sanyal

    (Uppsala University, BMC)

  • Maria Selmer

    (Uppsala University, BMC
    Uppsala University)

Abstract

The antibiotic resistance protein FusB rescues protein synthesis from inhibition by fusidic acid (FA), which locks elongation factor G (EF-G) to the ribosome after GTP hydrolysis. Here, we present time-resolved single–particle cryo-EM structures explaining the mechanism of FusB-mediated rescue. FusB binds to the FA-trapped EF-G on the ribosome, causing large-scale conformational changes of EF-G that break interactions with the ribosome, tRNA, and mRNA. This leads to dissociation of EF-G from the ribosome, followed by FA release. We also observe two independent binding sites of FusB on the classical-state ribosome, overlapping with the binding site of EF-G to each of the ribosomal subunits, yet not inhibiting tRNA delivery. The affinity of FusB to the ribosome and the concentration of FusB in S. aureus during FusB-mediated resistance support that direct binding of FusB to ribosomes could occur in the cell. Our results reveal an intricate resistance mechanism involving specific interactions of FusB with both EF-G and the ribosome, and a non-canonical release pathway of EF-G.

Suggested Citation

  • Adrián González-López & Xueliang Ge & Daniel S. D. Larsson & Carina Sihlbom Wallem & Suparna Sanyal & Maria Selmer, 2025. "Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58902-3
    DOI: 10.1038/s41467-025-58902-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58902-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58902-3?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. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. 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.
    3. Andreas H. Ratje & Justus Loerke & Aleksandra Mikolajka & Matthias Brünner & Peter W. Hildebrand & Agata L. Starosta & Alexandra Dönhöfer & Sean R. Connell & Paola Fucini & Thorsten Mielke & Paul C. W, 2010. "Head swivel on the ribosome facilitates translocation by means of intra-subunit tRNA hybrid sites," Nature, Nature, vol. 468(7324), pages 713-716, December.
    4. Emily J. Rundlet & Mikael Holm & Magdalena Schacherl & S. Kundhavai Natchiar & Roger B. Altman & Christian M. T. Spahn & Alexander G. Myasnikov & Scott C. Blanchard, 2021. "Structural basis of early translocation events on the ribosome," Nature, Nature, vol. 595(7869), pages 741-745, July.
    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. Timo Flügel & Magdalena Schacherl & Anett Unbehaun & Birgit Schroeer & Marylena Dabrowski & Jörg Bürger & Thorsten Mielke & Thiemo Sprink & Christoph A. Diebolder & Yollete V. Guillén Schlippe & Chris, 2024. "Transient disome complex formation in native polysomes during ongoing protein synthesis captured by cryo-EM," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. Zhao-Shan Chen & Hsiang-Chi Huang & Xiangkun Wang & Karin Schön & Yane Jia & Michael Lebens & Danica F. Besavilla & Janarthan R. Murti & Yanhong Ji & Aishe A. Sarshad & Guohua Deng & Qiyun Zhu & David, 2025. "Influenza A Virus H7 nanobody recognizes a conserved immunodominant epitope on hemagglutinin head and confers heterosubtypic protection," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    9. Sourav Nayak & Thomas J. Peto & Michal Kucharski & Rupam Tripura & James J. Callery & Duong Tien Quang Huy & Mathieu Gendrot & Dysoley Lek & Ho Dang Trung Nghia & Rob W. Pluijm & Nguyen Dong & Le Than, 2024. "Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    11. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    13. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    14. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    15. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    18. Young-Woo Nam & Dohyun Im & Ana Santa Cruz Garcia & Marios L. Tringides & Hai Minh Nguyen & Yan Liu & Razan Orfali & Alena Ramanishka & Grigore Pintilie & Chih-Chia Su & Meng Cui & Diomedes E. Logothe, 2025. "Cryo-EM structures of the small-conductance Ca2+-activated KCa2.2 channel," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    19. Florian Malard & Kristen Dias & Margaux Baudy & Stéphane Thore & Brune Vialet & Philippe Barthélémy & Sébastien Fribourg & Fedor V. Karginov & Sébastien Campagne, 2025. "Molecular basis for the calcium-dependent activation of the ribonuclease EndoU," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    20. Morié Ishida & Adriana E. Golding & Tal Keren-Kaplan & Yan Li & Tamas Balla & Juan S. Bonifacino, 2024. "ARMH3 is an ARL5 effector that promotes PI4KB-catalyzed PI4P synthesis at the trans-Golgi network," Nature Communications, Nature, vol. 15(1), pages 1-18, 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_s41467-025-58902-3. 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.