IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-12199-1.html
   My bibliography  Save this article

Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents

Author

Listed:
  • Praveen R. Juvvadi

    (Duke University Medical Center)

  • David Fox

    (Beryllium Discovery Corp.
    UCB Pharma.
    Seattle Structural Genomics Center for Infectious Disease (SSGCID))

  • Benjamin G. Bobay

    (Duke University Medical Center
    Duke University
    Duke University)

  • Michael J. Hoy

    (Duke University Medical Center)

  • Sophie M. C. Gobeil

    (Duke University
    Duke University)

  • Ronald A. Venters

    (Duke University Medical Center
    Duke University
    Duke University)

  • Zanetta Chang

    (Duke University Medical Center)

  • Jackie J. Lin

    (Duke University Medical Center)

  • Anna Floyd Averette

    (Duke University Medical Center)

  • D. Christopher Cole

    (Duke University Medical Center)

  • Blake C. Barrington

    (Duke University Medical Center)

  • Joshua D. Wheaton

    (Duke University Medical Center)

  • Maria Ciofani

    (Duke University Medical Center)

  • Michael Trzoss

    (Amplyx Pharmaceuticals)

  • Xiaoming Li

    (Amplyx Pharmaceuticals
    Forge Therapeutics, Inc.)

  • Soo Chan Lee

    (The University of Texas at San Antonio)

  • Ying-Lien Chen

    (National Taiwan University)

  • Mitchell Mutz

    (Amplyx Pharmaceuticals
    Genentech Inc.)

  • Leonard D. Spicer

    (Duke University Medical Center
    Duke University
    Duke University)

  • Maria A. Schumacher

    (Duke University)

  • Joseph Heitman

    (Duke University Medical Center)

  • William J. Steinbach

    (Duke University Medical Center
    Duke University Medical Center)

Abstract

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection.

Suggested Citation

  • Praveen R. Juvvadi & David Fox & Benjamin G. Bobay & Michael J. Hoy & Sophie M. C. Gobeil & Ronald A. Venters & Zanetta Chang & Jackie J. Lin & Anna Floyd Averette & D. Christopher Cole & Blake C. Bar, 2019. "Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12199-1
    DOI: 10.1038/s41467-019-12199-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-12199-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-12199-1?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
    ---><---

    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:10:y:2019:i:1:d:10.1038_s41467-019-12199-1. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.