5N18

Second Bromodomain (BD2) from Candida albicans Bdf1 bound to an imidazopyridine (compound 2)

Summary for 5N18

• Entry DOI: 10.2210/pdb5n18/pdb
• Descriptor: Bromodomain-containing factor 1, 4-[8-methyl-3-[(4-methylphenyl)amino]imidazo[1,2-a]pyridin-2-yl]phenol, GLYCEROL, ... (4 entities in total)
• Functional Keywords: bromodomain, transcription
• Biological source: Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast)
• Cellular location: Nucleus : Q5A4W8
• Total number of polymer chains: 2
• Total formula weight: 25674.16

Authors

Mietton, F.,Ferri, E.,Champleboux, M.,Zala, N.,Maubon, D.,Zhou, Y.,Harbut, M.,Spittler, D.,Garnaud, C.,Courcon, M.,Chauvel, M.,d'Enfert, C.,Kashemirov, B.A.,Hull, M.,Cornet, M.,McKenna, C.E.,Govin, J.,Petosa, C. (deposition date: 2017-02-05, release date: 2017-05-31, Last modification date: 2024-01-17)

Primary citation

Mietton, F.,Ferri, E.,Champleboux, M.,Zala, N.,Maubon, D.,Zhou, Y.,Harbut, M.,Spittler, D.,Garnaud, C.,Courcon, M.,Chauvel, M.,d'Enfert, C.,Kashemirov, B.A.,Hull, M.,Cornet, M.,McKenna, C.E.,Govin, J.,Petosa, C.
Selective BET bromodomain inhibition as an antifungal therapeutic strategy.
Nat Commun, 8:15482-15482, 2017

PubMed Abstract: Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

PubMed: 28516956
DOI: 10.1038/ncomms15482

Experimental method

X-RAY DIFFRACTION (1.45 Å)