ArticleNature communications2019
Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 122 citations in OpenAlex.
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- Resolving the ambiguous binding site of quercetin at the calcineurin subunit junction using funnel metadynamics with deep learning collective variables.Journal of computer-aided molecular design · 2026Article
- In Silico Analysis of Potential Stabilizer Binding Sites at Protein-RNA Interfaces.Computational and structural biotechnology journal · 2026Article
- Article
- Targeting calcineurin: a synergistic strategy with caspofungin to induce farnesol-mediated quorum sensing in Nakaseomyces glabrata-an inoculum-dependent tale.The Biochemical journal · 2025Article
- The sulfur-related metabolic status ofVirulence · 2025Article
- Cooperative Free Energy: Induced Protein-Protein Interactions and Cooperative Solvation in Ternary Complexes.Journal of chemical theory and computation · 2025Article
- Thermoregulation network governing virulence of a critical human fungal pathogen.bioRxiv : the preprint server for biology · 2025Article
- Research advancements in molecular glues derived from natural product scaffolds: Chemistry, targets, and molecular mechanisms.Chinese herbal medicines · 2025Review
- Structure-guided design and synthesis of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Recent innovations and challenges in the treatment of fungal infections.Frontiers in cellular and infection microbiology · 2025Review
- Calcineurin activity in Fonsecaea pedrosoi: tacrolimus and cyclosporine A inhibited conidia growth, filamentation and showed synergism with itraconazole.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
- Role of Hog1-mediated stress tolerance in biofilm formation by the pathogenic fungus Trichosporon asahii.Scientific reports · 2024Article
- Characterization and preparation of food-derived peptides on improving osteoporosis: A review.Food chemistry: X · 2024Article
- Drug to genome to drug: a computational large-scale chemogenomics screening for novel drug candidates against sporotrichosis.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
- Interdisciplinary approaches for the discovery of novel antifungals.Trends in molecular medicine · 2024Review
- Unlocking the function promiscuity of old yellow enzyme to catalyze asymmetric Morita-Baylis-Hillman reaction.Nature communications · 2024Article
- Targeting dermatophyte Cdc42 and Rac GTPase signaling to hinder hyphal elongation and virulence.iScience · 2024Article
- Advancements and challenges in antifungal therapeutic development.Clinical microbiology reviews · 2024Review
- Old and new strategies in therapy and diagnosis against fungal infections.Applied microbiology and biotechnology · 2024Review
3 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
22 authors at 7 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.