7ytv | pdb_00007ytv

Crystal structure of Aspergillus fumigatus Thioredoxin reductase in complex with auranofin

spinqualitylabelsall models 7ytv, resolution 3.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ytv is a 2 chain structure with sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.866Å Ligands: FAD, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A229Y1X4_ASPFM Publication Abstract from PubMed BACKGROUND: Infections caused by azole-resistant Aspergillus are a rising public health threat with high mortality rates, high treatment costs and limited available antifungals, indicating an urgent need for new antifungals or strategies. Our aim was to investigate antifungal and antibiofilm activities of auranofin, an FDA-approved anti-antirheumatic drug. METHODS: Fungal susceptibility testing for auranofin was carried out by the broth-based microdilution methods. Cell viability treated by auranofin was tested by resazurin dye testing. The synergistic effect of auranofin and antifungal drugs was evaluated using checkboard assay. The inhibitory of biofilms were measured by crystal violet staining. Gene expression level analysis and enzyme activity was investigated with qRT-PCR analysis and DTNB assay. The key amino acid residues in the binding of auranofin with A. fumigatus thioredoxin reductase (AfTrxR) were indicated by structural analyses, site-directed mutagenesis, and microscale thermophoresis (MST) assays. RESULTS: Auranofin has fungicidal activity and in vitro antifungal spectrum including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, even itraconazole (ITC)-resistant A. fumigatus. Additionally, it has antibiofilm activities against ITC-resistant A. fumigatus by reducing the expression level of SomA and MedA. Moreover, we discovered a synergistic effect of auranofin and ITC or amphotericin B against ITC-resistant A. fumigatus. Auranofin downregulated the gene transcription of AfTrxR, and strongly inhibited the enzyme activity of AfTrxR through interacting with residues C145 and C148. CONCLUSIONS: Auranofin has fungicidal and antibiofilm activities in Aspergillus spp. and is also a potentiator of ITC or amphotericin B in vitro. In vitro antifungal and antibiofilm activities of auranofin against itraconazole-resistant Aspergillus fumigatus.,Chen P, Yang J, Jin Y, Lu C, Feng Z, Gao F, Chen Y, Wang F, Shang Z, Lin W J Mycol Med. 2023 May;33(2):101381. doi: 10.1016/j.mycmed.2023.101381. Epub 2023 , Mar 28. PMID:37037064 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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