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

Publication ,  Journal Article
Juvvadi, PR; Fox, D; Bobay, BG; Hoy, MJ; Gobeil, SMC; Venters, RA; Chang, Z; Lin, JJ; Averette, AF; Cole, DC; Barrington, BC; Wheaton, JD ...
Published in: Nat Commun
September 19, 2019

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 19, 2019

Volume

10

Issue

1

Start / End Page

4275

Location

England

Related Subject Headings

  • Tacrolimus Binding Protein 1A
  • Tacrolimus
  • Molecular Dynamics Simulation
  • Mice, Inbred C57BL
  • Mice, Inbred A
  • Mice
  • Male
  • Female
  • Drug Discovery
  • Crystallography, X-Ray
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Juvvadi, P. R., Fox, D., Bobay, B. G., Hoy, M. J., Gobeil, S. M. C., Venters, R. A., … Steinbach, W. J. (2019). Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat Commun, 10(1), 4275. https://doi.org/10.1038/s41467-019-12199-1
Juvvadi, Praveen R., David Fox, Benjamin G. Bobay, Michael J. Hoy, Sophie M. C. Gobeil, Ronald A. Venters, Zanetta Chang, et al. “Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.Nat Commun 10, no. 1 (September 19, 2019): 4275. https://doi.org/10.1038/s41467-019-12199-1.
Juvvadi PR, Fox D, Bobay BG, Hoy MJ, Gobeil SMC, Venters RA, et al. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat Commun. 2019 Sep 19;10(1):4275.
Juvvadi, Praveen R., et al. “Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.Nat Commun, vol. 10, no. 1, Sept. 2019, p. 4275. Pubmed, doi:10.1038/s41467-019-12199-1.
Juvvadi PR, Fox D, Bobay BG, Hoy MJ, Gobeil SMC, Venters RA, Chang Z, Lin JJ, Averette AF, Cole DC, Barrington BC, Wheaton JD, Ciofani M, Trzoss M, Li X, Lee SC, Chen Y-L, Mutz M, Spicer LD, Schumacher MA, Heitman J, Steinbach WJ. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat Commun. 2019 Sep 19;10(1):4275.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 19, 2019

Volume

10

Issue

1

Start / End Page

4275

Location

England

Related Subject Headings

  • Tacrolimus Binding Protein 1A
  • Tacrolimus
  • Molecular Dynamics Simulation
  • Mice, Inbred C57BL
  • Mice, Inbred A
  • Mice
  • Male
  • Female
  • Drug Discovery
  • Crystallography, X-Ray