5b8i

Crystal structure of Calcineurin A and Calcineurin B in complex with FKBP12 and FK506 from Coccidioides immitis RS

spinqualitylabelsall models 5b8i, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5b8i is a 3 chain structure with sequence from Coccidioides immitis RS. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: CA, EDO, FE, FK5, MES, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function J3K8M7_COCIM Publication Abstract from PubMed 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. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.,Juvvadi PR, Fox D 3rd, 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 YL, Mutz M, Spicer LD, Schumacher MA, Heitman J, Steinbach WJ Nat Commun. 2019 Sep 19;10(1):4275. doi: 10.1038/s41467-019-12199-1. PMID:31537789 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Calcineurin 3D structures

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