Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents
| Autor: | Sophie M. C. Gobeil, Leonard D. Spicer, David A. Fox, Jackie J. Lin, Maria Ciofani, William J. Steinbach, Michael J. Hoy, Praveen R. Juvvadi, Ronald A. Venters, Blake C. Barrington, Zanetta Chang, Maria A. Schumacher, Anna F. Averette, Joseph Heitman, Michael Trzoss, Mitchell Mutz, Ying-Lien Chen, Joshua D. Wheaton, Xiaoming Li, Soo Chan Lee, Benjamin G. Bobay, D. Christopher Cole |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Antifungal Agents General Physics and Astronomy Tacrolimus Binding Protein 1A Crystallography X-Ray Aspergillus fumigatus Mice Candida albicans Drug Discovery polycyclic compounds lcsh:Science Cells Cultured Multidisciplinary biology Chemistry Calcineurin Cryptococcosis 3. Good health FKBP cardiovascular system Female Structure-based drug design Mice Inbred A Coccidioides immitis Science Calcineurin Inhibitors 030106 microbiology Virulence Molecular Dynamics Simulation Tacrolimus Article General Biochemistry Genetics and Molecular Biology Microbiology 03 medical and health sciences Hydrolase Animals Aspergillosis X-ray crystallography Cryptococcus neoformans Lead optimization Binding Sites Coccidioides organic chemicals General Chemistry biology.organism_classification Mice Inbred C57BL enzymes and coenzymes (carbohydrates) 030104 developmental biology lcsh:Q |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice. |
| Databáze: | OpenAIRE |
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