6Y35

CCAAT-binding complex from Aspergillus fumigatus with cycA DNA

Summary for 6Y35

• Entry DOI: 10.2210/pdb6y35/pdb
• Related: 4G91 4G92
• Descriptor: CCAAT-binding transcription factor subunit HAPB, CCAAT-binding factor complex subunit HapC, CCAAT-binding factor complex subunit HapE, ... (7 entities in total)
• Functional Keywords: transcription factor, heterotrimer, histone fold, protein:dna complex, transcription
• Biological source: Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100); More
• Total number of polymer chains: 5
• Total formula weight: 47443.01

Authors

Groll, M.,Huber, E.M. (deposition date: 2020-02-17, release date: 2020-05-27, Last modification date: 2024-01-24)

Primary citation

Hortschansky, P.,Misslinger, M.,Morl, J.,Gsaller, F.,Bromley, M.J.,Brakhage, A.A.,Groll, M.,Haas, H.,Huber, E.M.
Structural basis of HapE P88L -linked antifungal triazole resistance in Aspergillus fumigatus .
Life Sci Alliance, 3:-, 2020

PubMed Abstract: 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 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 mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the gene, which encodes the target of azoles, the 14-α sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists repression in low-iron environments and that this iron-dependent effect is lost in the HapE mutant. Altogether, these results indicate that the mutation HapE confers increased resistance to azoles compared with wt , particularly in low-iron clinical niches such as the lung.

PubMed: 32467317
DOI: 10.26508/lsa.202000729

Experimental method

X-RAY DIFFRACTION (2.6 Å)