6y35

CCAAT-binding complex from Aspergillus fumigatus with cycA DNA

spinqualitylabelsall models 6y35, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6y35 is a 5 chain structure with sequence from Aspergillus fumigatus A1163 and Aspergillus fumigatus Af293. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: SO3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q4X049_ASPFU Publication Abstract from PubMed Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole-resistant clinical Aspergillus fumigatus isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapE(P88L) mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the cyp51A gene, which encodes the target of azoles, the 14-alpha sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists cyp51A repression in low-iron environments and that this iron-dependent effect is lost in the HapE(P88L) mutant. Altogether, these results indicate that the mutation HapE(P88L) confers increased resistance to azoles compared with wt A. fumigatus, particularly in low-iron clinical niches such as the lung. Structural basis of HapE(P88L)-linked antifungal triazole resistance in Aspergillus fumigatus.,Hortschansky P, Misslinger M, Morl J, Gsaller F, Bromley MJ, Brakhage AA, Groll M, Haas H, Huber EM Life Sci Alliance. 2020 May 28;3(7). pii: 3/7/e202000729. doi:, 10.26508/lsa.202000729. Print 2020 Jul. PMID:32467317 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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