8R6J

Crystal structure of Candida glabrata Bdf1 bromodomain 1 bound to a pyrazole ligand

8R6J の概要

• エントリーDOI: 10.2210/pdb8r6j/pdb
• 分子名称: Candida glabrata strain CBS138 chromosome C complete sequence, 2-methyl-~{N}-[[5-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)thiophen-2-yl]methyl]pyrazole-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: bromodomain, transcription
• 由来する生物種: Nakaseomyces glabratus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 26833.13

構造登録者

Petosa, C.,Wei, K.,McKenna, C.E.,Govin, J. (登録日: 2023-11-22, 公開日: 2024-10-30, 最終更新日: 2025-03-26)

主引用文献

Wei, K.,Arlotto, M.,Overhulse, J.M.,Dinh, T.A.,Zhou, Y.,Dupper, N.J.,Yang, J.,Kashemirov, B.A.,Dawi, H.,Garnaud, C.,Bourgine, G.,Mietton, F.,Champleboux, M.,Larabi, A.,Hayat, Y.,Indorato, R.L.,Noirclerc-Savoye, M.,Skoufias, D.,Cornet, M.,Rabut, G.,McKenna, C.E.,Petosa, C.,Govin, J.
Humanized Candida and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors With Antifungal Potential.
Adv Sci, 12:e2404260-e2404260, 2025

PubMed Abstract: The fungal Bromodomain and Extra-Terminal (BET) protein Bdf1 is a potential antifungal target against invasive fungal infections. However, the need to selectively inhibit both Bdf1 bromodomains (BDs) over human orthologs and the lack of molecular tools to assess on-target antifungal efficacy hamper efforts to develop Bdf1 BD inhibitors as antifungal therapeutics. This study reports a phenyltriazine compound that inhibits both Bdf1 BDs from the human fungal pathogen Candida glabrata with selectivity over the orthologous BDs from the human BET protein Brd4. On-target antifungal activity is established by devising two yeast-based inhibition assays: a growth assay using humanized Candida strains in which the Bdf1 BDs are replaced by their Brd4 counterparts, and a NanoBiT assay that evaluates the BD-mediated association of Bdf1 with chromatin. These assays additionally enable the discovery that BET inhibitor I-BET726 targets both Bdf1 BDs, inhibits the growth of a broad spectrum of Candida species, including antifungal-resistant clinical isolates, and displays efficacy in an invertebrate animal model of infection. These collective findings highlight the promising potential of Bdf1 BD inhibitors as an innovative class of antifungal therapeutics and the pivotal role of yeast-based assay development toward achieving this end.

PubMed: 39821709
DOI: 10.1002/advs.202404260

実験手法

X-RAY DIFFRACTION (1.82 Å)