IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-53096-6.html
   My bibliography  Save this article

Structural basis for antibiotic transport and inhibition in PepT2

Author

Listed:
  • Joanne L. Parker

    (University of Oxford
    University of Oxford)

  • Justin C. Deme

    (National Cancer Institute)

  • Simon M. Lichtinger

    (University of Oxford)

  • Gabriel Kuteyi

    (University of Oxford)

  • Philip C. Biggin

    (University of Oxford)

  • Susan M. Lea

    (National Cancer Institute)

  • Simon Newstead

    (University of Oxford
    University of Oxford)

Abstract

The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport.

Suggested Citation

  • Joanne L. Parker & Justin C. Deme & Simon M. Lichtinger & Gabriel Kuteyi & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2024. "Structural basis for antibiotic transport and inhibition in PepT2," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53096-6
    DOI: 10.1038/s41467-024-53096-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-53096-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-53096-6?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. Keisuke Ito & Aya Hikida & Shun Kawai & Vu Thi Tuyet Lan & Takayasu Motoyama & Sayuri Kitagawa & Yuko Yoshikawa & Ryuji Kato & Yasuaki Kawarasaki, 2013. "Analysing the substrate multispecificity of a proton-coupled oligopeptide transporter using a dipeptide library," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
    2. Joanne L. Parker & Simon Newstead, 2014. "Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1," Nature, Nature, vol. 507(7490), pages 68-72, March.
    3. Leonhard X. Heinz & JangEun Lee & Utkarsh Kapoor & Felix Kartnig & Vitaly Sedlyarov & Konstantinos Papakostas & Adrian César-Razquin & Patrick Essletzbichler & Ulrich Goldmann & Adrijana Stefanovic & , 2020. "TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9," Nature, Nature, vol. 581(7808), pages 316-322, May.
    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. Tomalika R. Ullah & Matt D. Johansen & Katherine R. Balka & Rebecca L. Ambrose & Linden J. Gearing & James Roest & Julian P. Vivian & Sunil Sapkota & W. Samantha N. Jayasekara & Daniel S. Wenholz & Vi, 2023. "Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Xudong Chen & Min Xie & Sensen Zhang & Marta Monguió-Tortajada & Jian Yin & Chang Liu & Youqi Zhang & Maeva Delacrétaz & Mingyue Song & Yixue Wang & Lin Dong & Qiang Ding & Boda Zhou & Xiaolin Tian & , 2023. "Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Remzi Onur Eren & Göksu Gökberk Kaya & Robin Schwarzer & Manolis Pasparakis, 2024. "IKKε and TBK1 prevent RIPK1 dependent and independent inflammation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. repec:caa:jnlpse:v:preprint:id:398-2023-pse is not listed on IDEAS
    6. Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Xiaoqing Yuan & Yajun Li & Yan Shi, 2024. "Synergistic nitrogen fertiliser effects on nitrogen metabolism of wheat in saline-alkaline land," Plant, Soil and Environment, Czech Academy of Agricultural Sciences, vol. 70(6), pages 377-393.
    8. Tânia F. Custódio & Maxime Killer & Dingquan Yu & Virginia Puente & Daniel P. Teufel & Alexander Pautsch & Gisela Schnapp & Marc Grundl & Jan Kosinski & Christian Löw, 2023. "Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1," Nature Communications, Nature, vol. 14(1), pages 1-12, 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:15:y:2024:i:1:d:10.1038_s41467-024-53096-6. 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.