IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1003395.html
   My bibliography  Save this article

Utilizing a Dynamical Description of IspH to Aid in the Development of Novel Antimicrobial Drugs

Author

Listed:
  • Patrick G Blachly
  • César A F de Oliveira
  • Sarah L Williams
  • J Andrew McCammon

Abstract

The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsible for converting HMBPP to IPP and DMAPP in the ultimate step in the nonmevalonate pathway. By performing accelerated molecular dynamics simulations on both substrate-free and HMBPP-bound [Fe4S4]2+ IspH, we elucidate how substrate binding alters the dynamics of the protein. Using principal component analysis, we note that while substrate-free IspH samples various open and closed conformations, the closed conformation observed experimentally for HMBPP-bound IspH is inaccessible in the absence of HMBPP. In contrast, simulations with HMBPP bound are restricted from accessing the open states sampled by the substrate-free simulations. Further investigation of the substrate-free simulations reveals large fluctuations in the HMBPP binding pocket, as well as allosteric pocket openings – both of which are achieved through the hinge motions of the individual domains in IspH. Coupling these findings with solvent mapping and various structural analyses reveals alternative druggable sites that may be exploited in future drug design efforts.Author Summary: Drug resistance has recently entered into media conversations through the lens of MRSA (methicillin-resistant Staphylococcus aureus) infections, but conventional therapies are also failing to address resistance in cases of malaria and other bacterial infections, such as tuberculosis. To address these problems, we must develop new antibacterial and antimalarial medications. Our research focuses on understanding the structure and dynamics of IspH, an enzyme whose function is necessary for the survival of most bacteria and malaria-causing protozoans. Using computer simulations, we track how the structure of IspH changes in the presence and absence of its natural substrate. By inspecting the pockets that form in the normal motions of IspH, we propose a couple new routes by which new molecules may be developed to disrupt the function of IspH. It is our hope that these structural studies may be precursors to the development of novel therapies that may add to our current arsenal against bacterial and malarial infections.

Suggested Citation

  • Patrick G Blachly & César A F de Oliveira & Sarah L Williams & J Andrew McCammon, 2013. "Utilizing a Dynamical Description of IspH to Aid in the Development of Novel Antimicrobial Drugs," PLOS Computational Biology, Public Library of Science, vol. 9(12), pages 1-13, December.
  • Handle: RePEc:plo:pcbi00:1003395
    DOI: 10.1371/journal.pcbi.1003395
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003395
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1003395&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1003395?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. César Augusto F de Oliveira & Barry J Grant & Michelle Zhou & J Andrew McCammon, 2011. "Large-Scale Conformational Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics Simulation," PLOS Computational Biology, Public Library of Science, vol. 7(10), pages 1-7, October.
    2. Daniel-Adriano Silva & Gregory R Bowman & Alejandro Sosa-Peinado & Xuhui Huang, 2011. "A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein," PLOS Computational Biology, Public Library of Science, vol. 7(5), pages 1-11, May.
    3. Robert G. Ridley, 2002. "Medical need, scientific opportunity and the drive for antimalarial drugs," Nature, Nature, vol. 415(6872), pages 686-693, February.
    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. Shuo Gu & Daniel-Adriano Silva & Luming Meng & Alexander Yue & Xuhui Huang, 2014. "Quantitatively Characterizing the Ligand Binding Mechanisms of Choline Binding Protein Using Markov State Model Analysis," PLOS Computational Biology, Public Library of Science, vol. 10(8), pages 1-11, August.
    2. Yaqub, Ohid & Nightingale, Paul, 2012. "Vaccine innovation, translational research and the management of knowledge accumulation," Social Science & Medicine, Elsevier, vol. 75(12), pages 2143-2150.
    3. Polydefkis Diamantis & Oliver T Unke & Markus Meuwly, 2017. "Migration of small ligands in globins: Xe diffusion in truncated hemoglobin N," PLOS Computational Biology, Public Library of Science, vol. 13(3), pages 1-22, March.
    4. Lin-Tai Da & Fátima Pardo Avila & Dong Wang & Xuhui Huang, 2013. "A Two-State Model for the Dynamics of the Pyrophosphate Ion Release in Bacterial RNA Polymerase," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-9, April.
    5. Hanlun Jiang & Fu Kit Sheong & Lizhe Zhu & Xin Gao & Julie Bernauer & Xuhui Huang, 2015. "Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement," PLOS Computational Biology, Public Library of Science, vol. 11(7), pages 1-21, July.

    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:pcbi00:1003395. 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: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    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.