IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0217733.html
   My bibliography  Save this article

The molecular determinants of R-roscovitine block of hERG channels

Author

Listed:
  • Bryan Cernuda
  • Christopher Thomas Fernandes
  • Salma Mohamed Allam
  • Matthew Orzillo
  • Gabrielle Suppa
  • Zuleen Chia Chang
  • Demosthenes Athanasopoulos
  • Zafir Buraei

Abstract

Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine is a cyclin-dependent kinase (CDK) inhibitor that induces apoptosis in colorectal, breast, prostate, multiple myeloma, other cancer cell lines, and tumor xenografts, in micromolar concentrations. It is well tolerated in phase II clinical trials. R-roscovitine inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or hERG pore mutant channels (T623A, S624A, Y652A, F656A) demonstrated that compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 μM R-roscovitine was ~ 48%, 29%, and 73% weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with a ~ 34% stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. Docking studies further support our findings. Thus, R-roscovitine’s relatively unique features, coupled with its tolerance in clinical trials, could guide future drug screens.

Suggested Citation

  • Bryan Cernuda & Christopher Thomas Fernandes & Salma Mohamed Allam & Matthew Orzillo & Gabrielle Suppa & Zuleen Chia Chang & Demosthenes Athanasopoulos & Zafir Buraei, 2019. "The molecular determinants of R-roscovitine block of hERG channels," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-26, September.
  • Handle: RePEc:plo:pone00:0217733
    DOI: 10.1371/journal.pone.0217733
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217733
    Download Restriction: no

    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0217733&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pone.0217733?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. Youxing Jiang & Alice Lee & Jiayun Chen & Vanessa Ruta & Martine Cadene & Brian T. Chait & Roderick MacKinnon, 2003. "X-ray structure of a voltage-dependent K+ channel," Nature, Nature, vol. 423(6935), pages 33-41, May.
    2. Michael C. Sanguinetti & Martin Tristani-Firouzi, 2006. "hERG potassium channels and cardiac arrhythmia," Nature, Nature, vol. 440(7083), pages 463-469, March.
    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. Amrita X Sarkar & Eric A Sobie, 2010. "Regression Analysis for Constraining Free Parameters in Electrophysiological Models of Cardiac Cells," PLOS Computational Biology, Public Library of Science, vol. 6(9), pages 1-11, September.
    2. Ozer, Mahmut, 2005. "Determination of rate kinetics in ion channels by the path probability method and Onsager reciprocity theorem," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 357(3), pages 397-414.
    3. Turkan Haliloglu & Nir Ben-Tal, 2008. "Cooperative Transition between Open and Closed Conformations in Potassium Channels," PLOS Computational Biology, Public Library of Science, vol. 4(8), pages 1-11, August.
    4. Tobias Linder & Bert L de Groot & Anna Stary-Weinzinger, 2013. "Probing the Energy Landscape of Activation Gating of the Bacterial Potassium Channel KcsA," PLOS Computational Biology, Public Library of Science, vol. 9(5), pages 1-9, May.
    5. Spencer C. Guo & Rong Shen & Benoît Roux & Aaron R. Dinner, 2024. "Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Fang Du & Joseph J Babcock & Haibo Yu & Beiyan Zou & Min Li, 2015. "Global Analysis Reveals Families of Chemical Motifs Enriched for hERG Inhibitors," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-21, February.
    7. Shrivastava, Rajan & Malik, Chetan & Ghosh, Subhendu, 2016. "Open channel current noise analysis of S6 peptides from KvAP channel on bilayer lipid membrane shows bimodal power law scaling," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 451(C), pages 533-540.
    8. Joshua Mayourian & Ruben M Savizky & Eric A Sobie & Kevin D Costa, 2016. "Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes," PLOS Computational Biology, Public Library of Science, vol. 12(7), pages 1-29, July.
    9. Haiyan Mao & Xiaoli Lu & Justin Michael Karush & Xiaoyan Huang & Xi Yang & Yanna Ba & Ying Wang & Ningsheng Liu & Jianqing Zhou & Jiangfang Lian, 2013. "Pharmacologic Approach to Defective Protein Trafficking in the E637K-hERG Mutant with PD-118057 and Thapsigargin," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-12, June.
    10. Moniruzzaman & Mohammed Jabedul Hoque & Amrin Ahsan & Md Belayet Hossain, 2018. "Molecular Docking, Pharmacokinetic, and DFT Calculation of Naproxen and its Degradants," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 9(5), pages 7360-7365, October.
    11. Dahai Yu & Lin Lv & Li Fang & Bo Zhang & Junnan Wang & Ge Zhan & Lei Zhao & Xin Zhao & Baoxin Li, 2017. "Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells," PLOS ONE, Public Library of Science, vol. 12(8), pages 1-19, August.
    12. Jin Wang & Zeyuan Song & Miaolu He & Yongchao Qian & Di Wang & Zheng Cui & Yuan Feng & Shangzhen Li & Bo Huang & Xiangyu Kong & Jinming Han & Lei Wang, 2024. "Light-responsive and ultrapermeable two-dimensional metal-organic framework membrane for efficient ionic energy harvesting," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    13. Carlos A. Z. Bassetto & Flavio Costa & Carlo Guardiani & Francisco Bezanilla & Alberto Giacomello, 2023. "Noncanonical electromechanical coupling paths in cardiac hERG potassium channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    14. Marcos Matamoros & Xue Wen Ng & Joshua B. Brettmann & David W. Piston & Colin G. Nichols, 2023. "Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    15. Moniruzzaman & Mohammed Jabedul Hoque & Mohammad Nasir Uddin & Amrin Ahsan & Tareq Mahmud, 2018. "Quantum Chemical, Molecular Docking, and ADMET Predictions of Ketorolac and its Modified Analogues," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 11(5), pages 8723-8729, 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:plo:pone00:0217733. 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: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    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.